Graduate School of Medicine Kyoto University 2011

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Graduate School of Medicine

Kyoto University

2011

Graduate School of Medicine Kyoto University | 1

The Goal of the Graduate School of Medicine and Faculty of Medicine of Kyoto University– To develop a new realm of medical science and to create

innovative medical treatment.

Nagahiro MinatoDean of the Graduate School of Medicine and

Faculty of MedicineKyoto University

The Kyoto University Graduate School of Medicine offers four programs in which to major: Medicine, Medical Science, Public Health and Human Health Science. Each program can be taken to the masters and doctoral level (except for Medicine, which offers a doctorate only). The Graduate School is one of the largest in Japan, with an enrolment of 893 postgraduate students (as of October 2010). Our research domains cover the entire spectrum in medicine, healthcare and human health and welfare, including basic medicine, clinical medicine, social medicine and medical technology.

Our Graduate School has a mission: to educate international leaders who would engage in the drive to generate knowledge in the domains of medicine and healthcare and to contribute to the improvement of human health and welfare by continually deploying this knowledge to the world around us. Truly, we are living in an age of universalization and globalization. To accomplish our mission in this present-day context, we need an interdisciplinary approach. Extremely important is the discovery and development of new domains, through borderless interaction of enthusiastic students with diverse expertise and academic background, not only students who have basic training in the fields of medicine but also students who hail from non-medical disciplines.

In 2005, the Kyoto University Graduate School of Medicine became the first in Japan to initiate a new graduate training system. This Graduate Course of Integrated Research Training consists of some ten research areas (courses) relatively wide in universal scope. Students joining the Graduate School will choose one or more of these courses according to their own interests, regardless of the particular degree course or areas they are studying and irrespective of the boundaries of basic, clinical or social medicine. Regular research presentations and discussions are held, directing students into research activities that involve a broad perspective. Academic staffs also participate in one of the training courses according to their interests and expertise as individual researchers, regardless of the academic programs and specialist areas to which they appertain. The Course is principally run by students on a voluntary basis. Not only does it bring a broad perspective to research activities but it also has proved exceedingly useful in information exchange and promotion of new joint research projects within the Graduate School. The graduate teaching undertaken by the Graduate School consists of two main pillars: training through this Graduate Course of Integrated Research training and the conventional one-to-one research tutoring in specific research areas. We are confident that this framework is fully beneficial to the development of wide-ranging knowledge and research capacity of students. The Graduate School is a Global Center of Excellence (COE) designated by the Ministry of Education, Culture, Sports Science and Technology of the Japanese Government. The chief purpose of the COE is the pioneering of new research domains and globalization of research by means of collaboration and integration of many leading-edge research domains. As part of COE activities, we are sending our students overseas as well as receiving students from overseas, and we are establishing the practice of students giving seminars and research presentations in English.

I believe that the most important task of the Graduate School of Medicine is to train global leaders who can become the engines for progress in medicine and healthcare through their wide scientific knowledge and excellent research capacity and who can communicate with the world with originality. You all know well that we have a track record of producing world-class experts and brilliant research results. We hope that students who come to the Graduate School will join in our vigorous stream of research and success and be the very pioneers of the academia of the future.

2 | Graduate School of Medicine Kyoto University

Admission Policy··········································································· 4

Curriculum Policy ·········································································· 8

Diploma Policy ·············································································· 12

Research Field List ······································································· 14

Medicine (Doctoral Program)Medical Science(Master / Doctoral Program)

Basic Medicine (Core Departments)Biological Sciences ······································································· 28

Anatomy and Developmental Biology ··········································· 29

Anatomy and Cell Biology ···························································· 30

Physiology and Biophysics ··························································· 31

Pharmacology ·············································································· 32

Pathology and Tumor Biology ······················································· 33

Pathology and Biology of Diseases ·············································· 34

Diagnostic Pathology ···································································· 35

Microbiology ················································································· 36

Immunology and Cell Biology ······················································· 37

Forensic Medicine and Molecular Pathology ································ 38

Medical Chemistry ········································································ 39

Cell Biology ··················································································· 40

Molecular Oncology ······································································ 41

Molecular Genetics ······································································· 42

Radiation Genetics ······································································· 43

Morphological Brain Science ························································ 44

Integrative Brain Science ······························································ 45

Physiology and Neurobiology ······················································· 46

Cell Pharmacology ······································································· 47

Public Health ················································································ 48

Laboratory Animal Science(Institute of Laboratory Animals)··················································· 49

Congenital Anomaly Research Center ········································· 50

Human Disease Genomics (Center for Genomic Medicine) ···················································· 51

Genome Informatics (Center for Genomic Medicine) ···················································· 52

Medical Education (Center for Medical Education) ····················································· 53

Immunology and Genomic Medicine (Contributed Chairs) ····································································· 54

Statistical Genetics (Center for Genomic Medicine) ···················································· 55

Clinical Medicine (Core Departments)Hematology and Oncology ··························································· 56

Medicine and Clinical Science ······················································ 57

Cardiovascular Medicine ······························································ 58

Gastroenterology and Hepatology ················································ 59

Respiratory Medicine ···································································· 60

Rheumatology and Clinical Immunology ······································ 61

Geriatric Medicine ········································································ 62

Diabetes and Clinical Nutrition ····················································· 63

Primary Care and Emergency Medicine ······································· 64

Nephrology ··················································································· 65

Dermatology ················································································· 66

Pediatrics ······················································································ 67

Radiation Oncology and Image-Applied Therapy ························· 68

Diagnostic Imaging and Nuclear Medicine ··································· 69

Clinical Laboratory Medicine ························································ 70

Gastrointestinal Surgery ······························································· 71

Hepatopancreatobiliary Surgery and Transplantation ··················· 72

Breast Surgery ············································································· 73

Anesthesia ···················································································· 74

Gynecology and Obstetrics ·························································· 75

Urology ························································································· 76

Cardiovascular Surgery ································································ 77

Thoracic Surgery ·········································································· 78

Plastic and Reconstructive Surgery·············································· 79

Ophthalmology and Visual Sciences ············································ 80

Otolaryngology-Head and Neck Surgery ······································ 81

Orthopaedic and Musculoskeletal Surgery ··································· 82

Oral and Maxillofacial Surgery ······················································ 83

Clinical Molecular Biology ····························································· 84

Neurology ····················································································· 85

Neurosurgery ················································································ 86

Psychiatry ····················································································· 87

Transfusion Medicine and Cell Therapy ········································ 88

Diagnostic Pathology ···································································· 89

Medical Informatics ······································································· 90

Pharmacy ····················································································· 91

Experimental Therapeutics ··························································· 92

Clinical Trial Design and Management ········································· 93

Clinical Innovative Medicine ························································· 94

Brain Pathophysiology / Functional Brain Imaging(Human Brain Research Center) ·················································· 95

Organ Preservation Technology (Contributed Chairs) ····································································· 96

Multidisciplinary Cancer Treatment(Contributed Chairs)

Respiratory Care and Sleep Control Medicine (Contributed Chairs) ····································································· 97

Translational Clinical Oncology (Contributed Chairs) ····································································· 98

Translational Research CenterGhrelin Research Project ····························································· 99

Lactosome Project ········································································ 100

Radiation Biology CenterDepartment of Radiation System Biology (Laboratory of Genome Maintenance) ········································· 101

Department of Mutagenesis (Division of Chromatin Regulatory Network) ································ 102

Department of Late Effect Studies (Laboratory of DNA Damage Signaling) ······································ 103

Department of Genome Dynamics (Laboratory of Genome Dynamics) ············································· 104

Institute for Chemical ResearchChemical Biology ·········································································· 105

Institute for Frontier Medical SciencesMolecular and Cellular Biology ····················································· 106

INDEX


Ultrastructural Research ······························································· 107

Experimental Pathology ································································ 108

Immunobiology and Hematology ·················································· 109

Cellular Differentiation ·································································· 110

Development and Differentiation ·················································· 111

Growth Regulation ········································································ 112

Immunology ·················································································· 113

Tissue Regeneration ···································································· 114

Organ Reconstruction··································································· 115

Bioartificial Organs ······································································· 116

Nano Bioprocesses ······································································ 117

Medical Simulation Engineering ··················································· 118

Institute for Virus ResearchGene Analysis ·············································································· 119

Cell Regulation ············································································· 120

Laboratory of Human Tumor Viruses ············································ 121

Laboratory of Biological Protection ··············································· 122

Laboratory of Infection and Prevention ········································· 123

Laboratory of Growth Regulation ·················································· 124

Pathogenesis ················································································ 125

Viral Infections ·············································································· 126

Viral Pathogenicity ········································································ 127

Research Reactor InstituteRadiation Biology ·········································································· 128

Particle Radiation Oncology ························································· 129

Center for Southeast Asian StudiesPathogenic Microbiology······························································· 130

Field Medicine ·············································································· 131

Center for iPS Cell Research and Application (CiRA)Reprogramming Regulation Field ················································· 132

Differentiation Induction Field ······················································· 133

Disease modeling with patient-derived iPS cells ························· 134

Kyoto University Health ServicePreventive Services ······································································ 135

Institute for Integrated Cell-Material Sciences (iCeMS)Developmental Biology ································································· 136

Affiliate Graduate SchoolMedical Embryology (RIKEN Center for Developmental Biology) ·································· 137

Reproductive Biotechnology (RIKEN Center for Developmental Biology) ·································· 138

Developmental Biology (Osaka Bioscience Institute) ························································· 139

Application Biology and Regenerative Medicine(RIKEN Center for Developmental Biology) ·································· 140

Public Health(Professional Degree Program / Doctoral Program)

Biostatistics ··················································································· 141

Epidemiology and Healthcare Research ······································ 142

Pharmacoepidemiology ································································ 143

Human Disease Genomics (Center for Genomic Medicine) ···················································· 144

Healthcare Economics and Quality Management ························ 145

Medical Ethics / Medical Genetics ················································ 146

Health Informatics ········································································· 147

Medical Communication ······························································· 148

Management of Technology and Intellectual Property ·················· 149

Health and Environmental Sciences ············································· 150

Health Promotion and Human Behavior ······································· 151

Preventive Services ······································································ 152

Global Health and Socio-epidemiology ········································ 153

Public Health and International Health ········································· 154

Ecology with Emphasis on the Environment (Center for Southeast Asian Studies) ··········································· 155

Field Medicine (Center for Southeast Asian Studies) ··········································· 156

Human Health Science(Master / Doctoral Program)

Nursing ScienceEnvironmental Health Nursing ······················································ 157

Human Body Defense & Patho-physiology Nursing Science········ 158

Nursing Science for Lifestyle-Related Diseases ··························· 159

Psychiatric Nursing ······································································· 160

Critical Care Nursing ···································································· 161

Child Health and Development Nursing ········································ 162

Midwifery and Women's Health ···················································· 163

Female Life-Cycle Nursing

Preventive Nursing ······································································· 164

Public Health Nursing

Home Healthcare Nursing ···························································· 165

Laboratory ScienceBasic Laboratory Science ····························································· 166

Innovational Laboratory Medicine ················································· 167

Applied Laboratory Science ························································· 168

Medical Devices for Diagnoses ···················································· 169

Innovative Medical Imaging Technology ······································· 170

Medical Imaging System Sciences ··············································· 171

Rehabilitation SciencesMotor Function Analysis ······························································· 172

Development and Rehabilitation of Motor Funcition ····················· 173

Clinical Cognitive Neuroscience ··················································· 174

Brain Function and Rehabilitation ················································· 175

Fusion Unit for Near Future Human Health SciencesInnovation Unit for Near Future System and Technology ············· 176

Contact Information / Human Health Science ················································· 177

Access Guide ····························································· 179


Admission PolicyDoctoral (PhD) Program in Medicine

It is the solemn duty of medical researchers to unravel the mysteries of the human body, elucidate the mechanisms

that cause illness, and to apply this knowledge to the prevention and treatment of disease. Today we are witnessing

unprecedented momentum in the compartmentalization of medical fields, diversification and internationalization.

Therefore the burden of expectations placed upon medical researchers is now greater than ever. Modern medical

researchers must not only possess unsurpassed knowledge in their respective fields of expertise, but broadening

their horizons to the diverse array of academic sub-specialties is implied in their occupational mandate.

Additionally, to become a truly well-rounded medical researcher in the era of globalization, one must be able

to establish collaboration with other laboratories, and make an invaluable contribution to the international

community. This is our vision for the researchers we hope to develop in the Graduate School of Medicine, PhD

(Medicine) program.

Based on this vision, what started off as 6 independent research fields within the Graduate School of Medicine

were consolidated in 2006 to help promote interdisciplinary interaction. In addition to traditional classroom

instruction and training seminars, we introduced the Graduate School Training Course which bridges the gap

between Clinical, Basic and Social Medicine. The PhD program offers this and other programs that place PhD

candidates at their core. By nurturing the autonomy of PhD candidates, we hope to develop researchers who will

lead medical research towards unprecedented progress in the 21st century. Individuals with demonstrated superior

academic achievements actively seeking to put their knowledge and technical skills to use in the field of medical

research are strongly encouraged to apply.

Master of Science (MS) Program in Medical Science

The Master of Science (MS) program in Medical Science was established for the noble purpose of developing

highly qualified researchers in the field of medical science that meet the highest of professional and ethical

standards. Consequently, candidates enrolled under the MS (Medical Science) degree program with no background

in the natural sciences will be required to successfully negotiate a rigorous training regimen structured largely

upon challenging classroom instruction in the fields of basic medical science, and complete intensive training

in medical science research. As with all other programs offered under the Graduate School of Medicine, degree

candidates will be exposed to a highly competitive, yet equally fulfilling academic environment that constantly

redefines their cognitive potential.

The MS program at the Graduate School of Medicine boasts an open stance on admissions and actively seeks

highly motivated individuals representing diverse academic backgrounds to conduct pioneering research in

medical research at one of the world’s most prominent research institutions.


Doctoral (PhD) Program in Medical Science

Our rapidly evolving understanding of the life sciences has resulted in swift changes in the healthcare and medical

environments. With that, research and educational initiatives within the medical community has also become

increasingly more advanced and complex. Until now, the traditional medical education system revolved around

the development of medical practitioners; however, with remarkable advances in our understanding of the life

sciences, it is imperative that medical professionals effectively make use of this information for transition into

novel therapeutic techniques.

We are now witnessing drastic changes in the way physicians diagnose patients. Today more than ever, physicians

are relying heavily upon advanced medical devices for diagnostic assistance. Research encompassing these

medical devices and diagnostic techniques are actively being conducted on a daily basis, and carry with them the

hopes and dreams of a quickly aging population.

As society’s pinnacle of research and education, developing aggressive researchers to venture beyond the

framework of traditional medical education and research is the solemn mission assigned to all universities.

In the PhD (Medical Science) program, we answer society’s call by bringing together individuals who have

demonstrated superior academic achievement in the natural sciences and engineering, and training them on the

many diverse perspectives of medicine to become the world’s leading researchers/educators in medical science.

Professional Degree Program in School of Public Health

This program is structured specifically for students who wish to seek a future in public health, medicine or

welfare, as an educator or technical specialist. Students enrolled in this program will receive training to acquire

knowledge, technical skills and professionalism in the field of Public Health. Upon completion of training,

graduates will be able to detect, evaluate, analyze and problem-solve the many public health issues that plague

the “health of our society” today. Because the program provides an assortment of academic fields to specialize

in—everything from the natural sciences to human social science—our policy on admissions are very open, and

qualified individuals from all walks of life are encouraged to apply. We welcome highly motivated applicants

from various academic disciplines who display a strong conviction to be an advanced professional or educator/

researcher in health, medicine, and welfare in Japan and abroad.

Management of Technology and Intellectual Property Course (Est. 2004)Japan is quickly becoming oriented to the international race for intellectual property rights and is active in

the application of patents in the medical field. Therefore, Japan is in need of advanced professionals who can

secure and manage the intellectual property rights of advanced medical research initiatives when they bear fruit.

Applicants eager to pursue a future in intellectual asset management are encouraged to apply.


Clinical Researcher Training Course (Master of Clinical Research, MCR; Est. 2005)The MCR is an intensive 1-year program designed specifically for medical doctors and dentists. Until now, the

majority of medical research conducted in Japan revolved primarily around the life sciences; however, there is a

growing understanding now on the importance of human and population based clinical studies. The MCR is the

first program of its kind to be offered in Japan, and is devoted to training medical professionals who will assume

future careers as physician-scientists. Applications are openly welcome from individuals who have nurtured an

interest in conducting clinical research based on their own clinical experiences.

Genetic Counseling and Clinical Research Unit (Est. 2006)In actuality, this program stems from two distinct courses: the Genetic Counseling Course and the Clinical

Research Unit. Our mission is to train genetic counselors and clinical research coordinators who are intellectually

capable, are well-versed, and can lead future initiatives in frontier medicine. Using the skills honed in these

programs, our graduates will serve as an interface between novel medical techniques and those who will directly

benefit from these techniques (patients, families, and research subjects). Individuals with a strong pioneering spirit

and eager to conduct frontier clinical research are encouraged to apply.

Doctoral (PhD) Program in School of Public Health

This course aims at developing researchers who will focus on the detection, evaluation, analysis, and resolution

of the countless health issues that compromise “the health of society”. Students who complete this course are

expected to engage in advanced education/research initiatives in public health, medicine, and welfare not only

in Japan, but in other countries as well. This course is truly multidisciplinary, covering an assortment of fields

from the natural sciences to the human social sciences. Therefore, we welcome applicants carious academic

backgrounds who are eager to perform research on public health issues.


Master of Science (MS) Program in School of Human Health Science

While we have witnessed much progress over the years in our understanding of Medicine and its application

to various avenues of treatment, further evolution is imperative in meeting the medical demands of the future.

The Graduate School of Medicine at Kyoto University has long-since been a forerunner in pushing forward the

advancement of medical technology. To ensure that generations to come will have open access to high quality

public health, medical care, and welfare in Japan, we proposed the creation of a new scientific field called Human

Health Sciences. The MS program at the School of Human Health Science logically defines the concept of “health”

it strives to pursue, and provides extensive training and education in order to secure the demand for highly

qualified future healthcare professionals. Based on these principles, we provide healthcare providers with superior

clinical and communication skills who can provide superior medical care that meets the demands of patients.

Additionally, we combine basic and clinical medicine, along with other academic disciplines and intellectual

assets at Kyoto University to develop future educators and researchers. Individuals with a passion for supporting

the healthcare efforts of the future are encouraged to apply.

Doctoral (PhD) Program in School of Human Health Science

Throughout its proud heritage, Kyoto University has always assumed a central role in the prevention and treatment

of disease. The PhD program at the School of Human Health Science was established for the humble purpose

of nurturing professionals who can promote the concept of genuine health, establish a theoretical foundation

for research in the field of Human Health Sciences, and apply this theoretical foundation into actual practice

to overcome disease. In order to maintain its leadership role in the field of medicine/medical science, Kyoto

University requires PhD candidates to explore beyond the reaches of their respective areas of expertise, and

actively seek knowledge in a wide array of academic fields that will enable them to assume leadership roles in

multi-disciplinary environments. To this end, the Merger Unit for Future Human Health Sciences—consisting of

an orchestra of researchers representing the fields of medicine, engineering, pharmacology, the natural sciences,

social studies, and the humanities—was established in order to promote novel theories and practices for physical

and psychological diagnosis, patient treatment, and the sustenance of daily health. Given our future perspective,

it is our mission to develop experts who will become leaders in the ever-evolving field of Human Health Science.

Therefore, it is our hope to not only attract individuals with a background in Medicine and the Medical Sciences,

but also those representing the public and private sectors. Upon completion of studies at the School of Human

Health Science, graduates will return to the industrial, public and academic domains as invaluable assets. Highly

qualified and motivated individuals are actively sought for this program.


Curriculum PolicyCurriculum in Medicine

In the PhD program, students will select their own respective posts of assignment from an assortment of renowned

departments and laboratories at the Graduate School of Medicine, Kyoto University. It is there that prospective

PhD candidates will acquire the fundamental skills and knowledge required to plan, conduct and complete a

respectable project in basic and clinical medical research. PhD candidates will also be assigned to at least one of

the Graduate School Training Courses, which bridges the gap between Clinical, Basic and Social Medicine.

In the Graduate School Training Course, degree candidates will hone their knowledge and sense of ethics as future

researchers, and further benefit from periodic interactive seminars with professors where ideas can be freely

exchanged. Through this active exchange, students will gain a broader perspective on the concept of medical

research, and learn to nurture vital skills in establishing collaboration, which will enable them to erect new

avenues of research.

Using this approach based on comprehensive training in the fundamental principles of medical science and

emphasizing the importance of teamwork, it is our sincerest hope that the graduates of this program will

transcend the boundaries that inhibit collaboration amongst researchers, and become the world’s leading medical

researchers/educators.

Curriculum in Medical Science

Under the Master of Science (MS) program, students with no background in medicine receive instruction in

the basic medical sciences and training in research methodologies to become broad-minded and extraordinary

researchers in the challenging field of medicine. In just 2 years, students with no background in the biological

sciences will acquire a working and fundamental understanding of the natural sciences via the comprehensive

coursework offered under this program. The initial 4-month period in the MS program will be devoted to intensive

classroom instruction in the essential sciences and laboratory training. After this phase, students will select one

laboratory—from an assortment of more than 110—to conduct research throughout the remainder of their MS

candidacies, where their knowledge and skills acquired in other academic disciplines will be utilized to the fullest

extent.

On the other end of the spectrum, students enrolled in the PhD program will be directly assigned to their

laboratory-of-choice upon entrance, where they will receive continuous training on how to plan and complete a

medical research project on their own. To supplement their training, PhD candidates will also be assigned to one

of the Graduate School Training Courses, which bridges the gap between Basic, Clinical and Social Medicine.

In the Graduate School Training Course, PhD candidates will broaden their horizons via exposure to students

and staff representing other fields of medical expetise. Through these interactions, PhD candidates will acquire a


broader perspective and learn first-hand the importance of establishing collaboration on the sometimes arduous

road to discovering uncharted territories in the field of medicine.

Based on this approach combining comprehensive instruction in the fundamental medical sciences and

emphasizing the importance of collaboration, the PhD program aims to develop highly competent researchers

that will transcend the boundaries of compartmentalization and become the world’s leading medical researchers/

educators.

Curriculum in School of Public Health

The professional degree program offered under the School of Public Health is designed to develop multifaceted

professionals who will pursue a career in public health, medicine or welfare. Upon completion of the program,

graduates will be able to detect, evaluate, analyze and problem-solve the many public health issues that

threaten the health of society’s key component—the individual. To develop fully capable professionals, we

offer a curriculum based on comprehensive instruction in the fundamental subjects, training to apply acquired

knowledge to real-world situations, and hands-on training. Instruction in the “fundamental subjects” implies the

core principles (epidemiology, medical statistics, environmental science, administration/management, and social

science) of science that all experts hold as common ground in the field of Public Health. For graduates with no

background in medicine, we provide extensive training in subjects covering basic and clinical medical subjects.

In addition to providing instruction on the fundamental principles of medicine, we offer “applied learning” which

comes in the form of diverse electives and includes everything from courses in the frontier medical sciences

to human social sciences. In terms of “practical training,” every student is assigned a topic for a subjective

study. Under this segment of training, students will plan a project, evaluate the ethical considerations, conduct

experiments and present their findings in the same fashion as professional researchers.

To augment the traditional, systematic coursework and curricula, the School of Public Health established three

special training courses to develop professionals in highly technical fields.

Management of Technology and Intellectual Property CourseThis course was established for the sole purpose of developing professionals who can manage the end product of

frontier medical research, as intellectual assets. Students electing this course will acquire specialized knowledge in

intellectual property rights and technical management practices. In order to develop highly qualified professionals,

the Management of Technology and Intellectual Course provides practical training in patenting, establishing an

invention, screening for existing patents, making invoices, business planning and contract writing, in addition to

standard classroom instruction in biology, medicine, technical management and law (intellectual property law,

patent law).


Clinical Researcher Training Course (Master of Clinical Research, MCR)Designed specifically for medical doctors and dentists, the Clinical Researcher Training Course is a one-year

intensive course to develop highly qualified clinically-oriented epidemiological researchers. Upon graduation,

students enrolled under this program will be highly proficient in erecting a concept for a clinical research

project based on their own personal experiences, and establish relevant research protocols, manage and conduct

experiments, analyze data, interpret the results and prepare a manuscript detailing the contents of the project.

Genetic Counseling and Clinical Research Unit This is a combined program composed by the Genetic Counseling and Clinical Research Units. In either unit,

the mission is to train genetic counselors and clinical research coordinators who are intellectually capable, well-

versed, and can lead future initiatives in frontier medicine. Graduates will serve as an interface between novel

medical/therapeutic techniques, and their beneficiaries (patients, families, and research subjects). Through a

combination of traditional classroom instruction and practical training, graduates of the Genetic Counseling

and Clinical Research Units will have acquired the knowledge and skills required to successfully negotiate the

Certified Genetic Counselor examination and Clinical Coordinator certification examination (administered by the

Japan Clinical Pharmacology Association), respectively.

The doctoral (PhD) degree program offered under the School of Public Health is designed to provide training in

all essential subject areas and technical skills, and strengthens the mental fortitude of degree candidates who seek

a future in Public Health. Upon completion of the program, graduates will be able to detect, evaluate, analyze and

problem-solve the many public health issues that threaten the health of society’s key component—the individual.

The expectations that society has of Public Health professionals are high. Therefore, the PhD curriculum is content

in offering advanced education and training initiatives in public health that will make its graduates competitive

on the global arena. PhD candidates who did not complete the professional degree program offered at the Kyoto

University School of Public Health, are obligated to complete coursework in the core subject areas (epidemiology,

medical statistics, environmental science, administration/management, and social science). PhD candidates with

no background in medicine will also be required to complete courses in basic medicine and clinical medicine in

order to ensure the high standard of quality that graduates of Kyoto University are synonymous for.

Curriculum in School of Human Health Science

To ensure that generations to come will have open access to high quality public health, medical care, and welfare

in Japan, we proposed the creation of a new scientific field called Human Health Sciences.

The MS program at the School of Human Health Science aims to push forward the momentum of advanced

frontier medicine, and seeks to secure a solid foundation of healthcare, welfare and social insurance for future

generations. Additionally, the School of Human Health Science logically defines the concept of “health” it strives

to pursue for future generations, and provides extensive training and education in order to fulfill this goal. The

MS program offers courses in Nursing Science, Laboratory Analysis and Rehabilitation Science. In either course,

MS candidates will be expected to meet the highest standards of professionalism and demonstrate a high degree of


knowledge in Human Health Science. Through diverse curricula, the MS course hopes to develop researchers who

can bridge the gap between basic and clinical medicine, and can establish cooperative projects with laboratories

representing various academic disciplines in the hopes of making unprecedented progress in the unexplored

reaches of human health science.

The PhD program at the School of Human Health Science was established for the humble purpose of nurturing

professionals who can promote the concept of genuine health, establish a theoretical foundation for research in

the field of Human Health Sciences, and apply this theoretical foundation into actual practice to overcome the

constant threat of disease. In order to assume a central role in the field of human health sciences, a PhD candidate

must not only be proficient in his/her domain of expertise, but must also possess administrative and managerial

skills in a variety of disciplines. To this end, the Merger Unit for Future Human Health Sciences—consisting of

an orchestra of researchers representing the fields of medicine, engineering, pharmacology, the natural sciences,

social studies, and the humanities—was established in order to promote novel theories and practices for physical

and psychological diagnosis, patient treatment, and the sustenance of daily health. PhD candidates will be

provided with ample training and education that will enable them to become future leaders in the constantly

evolving field of Human Health Science.


Diploma PolicyDegrees in Medicine

Under the PhD program, students will receive 4+ years of intensive post-graduate training. During this time,

degree candidates must complete at least 24 units in subject courses, at least 6 units in Graduate School Training

Courses, and have a manuscript published as the first author in a peer-reviewed international journal of prominent

standing. Lastly, PhD candidates must successfully negotiate an oral thesis defense prior to being conferred upon

the PhD degree.

Degrees may be awarded upon completion of the 3rd (or midway through the 4th) year of PhD studies under

special circumstances in which a candidate’s absolute independence as a researcher has been clearly demonstrated.

To qualify under this special provision, a candidate must demonstrate his/her ability to erect a concept for a

medical research project, and be able to plan, implement and compile the results of the project in a manuscript of

impeccable quality. Furthermore, the manuscript must be published in a prominent journal of exceptional standing

within the global scientific community for consideration under this provision. After these requisites have been

met, a candidate will next be administered a written PhD aptitude battery. Final conference of degrees will be

determined following the candidate’s satisfactory completion of the aptitude battery.

Degrees in Medical Science

Under the Master of Science (MS) program, students must receive 2+ years of training, and will be required to

complete at least 30 units in subject courses (in addition to completing subjective studies). Additionally, a master’s

thesis detailing the candidate’s research topic must be submitted for review, and will be followed by an oral thesis

defense prior to being conferred upon the MS degree.

Candidates under the PhD program must be enrolled and receive training in research for 3+ years, and are required

to complete at least 11 units of graduate coursework (7 in major subjects, and 4 in minor subjects). Additionally,

PhD candidates must have a manuscript published (as the first author) in a peer-reviewed international scientific

journal of prominent standing and are required to undergo an oral thesis defense on the candidate’s published work

prior to being awarded the PhD degree.

Degrees in School of Public Health

Candidates applying for a professional degree under the Public Health program must receive 2+ years of training,

and complete at least 30 units in subject courses (in addition to completing subjective studies). Those enrolled

under the “special course” must meet additional requirements regarding compulsory courses. The topic of

the subjective study shall be determined by—and executed at—the laboratory in which the candidate resides.

Subjective studies will mold a solid concept of research in degree candidates via intensive first-hand training in

establishing research protocols, data acquisition and analysis, and interpreting the results of a study. In addition to


completing the required coursework and subjective study, candidates must pass an oral thesis defense in order to

be conferred upon the professional degree in Public Health.

Candidates under the Public Health PhD program must be enrolled and receive training for a period of 3+

years, in which time candidates will be responsible for completing required coursework. The minimum amount

of coursework units required for graduation depends upon a candidate’s academic background. Holders of

professional degrees awarded in Public Health by Kyoto University need only complete 6 units of coursework.

For graduates of institutions other than Kyoto University: those awarded degrees in subjects related to Medicine

must complete 13 or more units, and those awarded degrees in non-medical subject areas must complete 19 or

more units. Additionally, PhD candidates must have a manuscript published (as the first author) in a peer-reviewed

international scientific journal of prominent standing and are required to undergo an oral thesis defense on the

candidate’s published work prior to being awarded the PhD degree.

Degrees in School of Human Health Science

Candidates under the Human Health Science MS program must be enrolled for a period of 2+ years and complete

a minimum of 30 units of coursework in subjects consistent with the educational philosophy of the School of

Human Health Science. Additionally, candidates must receive ongoing research training, submit a Master’s thesis

and pass an oral thesis defense. Required coursework falls into one of four major subject classifications: Major

required subjects, general required subjects, electives and special research assignments. A candidate can obtain

coursework units by attending lectures, seminars, labs, clinical training sessions and field work.

CNS program candidates must be enrolled for a period of 2+ years and complete a minimum of 32 units of

coursework in (cancer CNS) subjects consistent with the educational philosophy of the School of Human Health

Science. Additionally, candidates must submit a Master’s thesis and pass an examination administered by the

School of Human Health Science.

A panel of judges will comprehensively evaluate a Master’s thesis based on criteria such as novelty, academic

significance, creativity and practical applicability. Similarly, in addition to being evaluated on research progress,

ethical considerations, and ability to logically present the outcome of a study, degree candidates will be tested in

order to confirm that they possess ample knowledge in the field of study.

Candidates accepted under the Human Health Science PhD program must be enrolled for a period of 3+ years and

complete a minimum of 16 units of coursework (special lectures, special seminars, merger unit courses and special

research assignments) in subjects consistent with the educational philosophy of the School of Human Health

Science. Additionally, candidates must receive ongoing research training, submit a PhD thesis and pass an oral

thesis defense.

A panel of judges will comprehensively evaluate a PhD thesis based on criteria such as novelty, academic

significance, creativity and practical applicability. Similarly, in addition to being evaluated on research progress,

a candidate must hold to the highest standards of ethics, and must demonstrate the ability to logically present the

outcome of a study. Furthermore, degree candidates will be tested in order to confirm that they possess ample

knowledge in subjects encompassing the field of study. Only those who successfully meet all of the defined

requirements will be awarded the PhD degree.


Research Field List

Research Field Professor Area of Research

Biological Sciences Dai WATANABE

Study of functional brain development ●

Study of information processing in the brain ●

Study of sensori-motor integration ●

Anatomy and Developmental Biology

Masatoshi HAGIWARA

Study of morphogenesis and differentiation ●

Decipherment of splicing code ●

Development of new drugs to cure RNA diseases ●

Anatomy and Cell Biology Mitinori SAITOU

Study of origin, properties, and regulation of the germ cell lineage ●

Molecular mechanisms of epigenetic reprogramming in vivo and in vitro ●

Study of in vitro reconstruction of germ cell development ●

Molecular mechanisms of self renewal of stem cells ●

Physiology and Biophysics

Molecular mechanism of cardiac muscle cell function ●

Molecular control mechanism of ion channel function ●

Blood circulation control system ●

Pharmacology Makoto Mark TAKETO

Molecular genetic study of cancers of digestive organs using knockout mice ●

Study of cancer microenvironment in invasion and metastasis ●

Search for cancer therapeutics based on above studies ●

Pathology and Tumor Biology

Study of molecular mechanism of individual aging ●

Molecular biology of neuronetwork formation ●

Study of molecules controlling formation, maintenance, and differentiation of reproductive ●

cells

Study of molecular mechanism of axial formation in mammalian embryo ●

Study of human pathology, cancer control genes, and carcinogenesis mechanism ●

Pathology and Biology of Diseases

Michiyuki MATSUDA

Live cell imaging of growth factor signal transduction network ●

Study of cancer cell invasion and metastasis with live cell imaging techniques ●

Systems analysis of oncogene signaling network ●

Diagnostic Pathology Hironori HAGA

Pathological diagnostics (surgical pathology) and cytodiagnosis ●

Clinicopathological study using surgical pathological materials ●

Application of immunohistochemistry to pathology ●

Computerization of pathological diagnostic tasks ●

Microbiology Masao MITSUYAMA

Molecular mechanism of intracellular parasitism of bacteria (Listeria and Mycobacteria) ●

Study of Immune response of the host against bacterial infection ●

Mechanism of virulence factor-dependent cytokine response ●

Biochemical study on cholesterol-dependent cytolysins ●

Immunology and Cell Biology Nagahiro MINATO

Development and regulation of immune cells and tissues ●

Small G protein signaling in normal development of lymphocytes and leukemia genesis ●

Mechanisms of anti-tumor immunity and its application ●

Regulation of hematopoiesis and myeloproliferative disorders ●

Forensic Medicine and Molecular Pathology

Keiji TAMAKI

Forensic genetics ecompassing human DNA polymorphisms ●

Study of instability in tandem repeat sequences ●

Retroviral and pathological assessment of blastic B-cell lymphoma ●

Medical Chemistry Shigekazu NAGATA

Molecular mechanism of cell death ●

Engulfment of dead cells, and its abnormality ●

Assymmetrical distribution of phospholipids in plasma membrane ●

Cell Biology So IWATA

X-ray crystallography on membrane proteins ●

Structure and mechanism of G-protein coupled receptors ●

Structure and Mechanism of membrane transporters ●

Molecular Oncology Makoto NODA

Molecular mechanisms of carcinogenesis ●

Roles of RECK, a membrane anchored MMP regulator, in development and diseases ●

Genes and chemicals suppressing malignant phenotypes of tumor cells ●

Molecular Genetics Takashi SHINOHARAStudy of development and control of stem cell system ●

Reproductive engineering using spermatozoon stem cells ●

Medicine (Doctoral Program) / Medical Science (Master /Doctoral Program)

Basic Medicine (Core Departments)



Radiation Genetics Shunichi TAKEDA

Hereditary factors related to carcinogenesis ●

Mechanism of acquisition of resistance to radio-/chemotherapy of cancers ●

Gene therapy using homologous DNA recombination ●

Mechanism of maintenance and inheritance of chromosomal DNA ●

Screening of environmental carcinogenic chemicals ●

Morphological Brain Science Takeshi KANEKO

Experimental morphological and theoretical study of cerebral cortex nerve circuit ●

Electrophysiological and morphological study of local circuit of the central nervous system ●

Experimental morphology of neuronal connection of the central nervous system ●

Experimental morphology of circuit formation of the central nervous system ●

Experimental morphology of neuroactive substances and receptors ●

Integrative Brain Science Kenji KAWANO

Study of information processing system of the brain ●

Study of neuronal mechanism of visual control of movement ●

Study of higher brain function ●

Physiology and Neurobiology Harunori OHMORIFunctional study of synapses of the central nervous system ●

Feature extraction and processing of auditory information ●

Cell Pharmacology Shuh NARUMIYA

Study of role of prostaglandin receptors in chronic inflammation and diseases ●

Study of emotional behavior and its abnormality under stress ●

Study of cellular function of small G protein Rho and its role in the body ●

Study of role of cytoskeletal dynamics in neuronal plasticity ●

Public Health Toshitaka NAKAHARA

Study of health policy ●

Study of international health ●

Study of health promotion and health education ●

Laboratory Animal Science(Institute of Laboratory Animals)

Tadao SERIKAWA

Development and genetic analysis of disease model animals ●

Development of genetically modified rat strains ●

Study of rat strain characteristics ●

Congenital Anomaly Research Center

Keiji TAMAKI

Malformation ●

Molecular cell biological study of mechanism of abnormal development ●

Hereditary epidemiological study of causes of malformation ●

Reproductive and developmental toxicology ●

Human Disease Genomics(Center for Genomic Medicine)

Fumihiko MATSUDA

Identification of genetic factors related to human multifactorial diseases ●

Genetic epidemiology of community-based prospective genome cohorts ●

Development of database for the management of genomic studies ●

Genome Informatics(Center for Genomic Medicine)

Comparative genomic study on gene regulation ●

Bioinformatics analysis of splice regulation ●

High-throughput gene expression data analysis on cancer cells ●

Medical Education(Center for Medical Education)

Coordination of undergraduate and postgraduate medical education ●

Coordination of faculty development and staff development for medical education ●

Coordination of interprofessional education in the medical field ●

Study of learning sciences for medical education ●

Study of patient safety ●

Study of resuscitation science and prehospital care ●

Study of communication for medical interview ●

Immunology and Genomic Medicine(Contributed Chairs)

Tasuku HONJO

Study on molecular mechanisms for immunoglobulin diversification ●

Study on genomic instability related to immunoglobulin gene alteration ●

Study on immune-regulatory mechanism of costimulatory molecules ●

Statistical Genetics(Center for Genomic Medicine)

Ryo YAMADADevelopment of methods in phenotye mapping ●

Study of genetic polymorohpisms and heterogeneity ●


Research Field List


Hematology and Oncology Akifumi TAKAORI

Basic and clinical studies of tumors of hematopoietic organs ●

Study of pathophysiology of anemia ●

Study of pathophysiology of iron metabolism ●

Study of pathology and control of infectious diseases ●

Basic and clinical studies of cellular immunotherapy ●

Study of differentiation and function of blood cells ●

Basic study of gene therapy ●

Medicine and Clinical Science Kazuwa NAKAO

Study of causes, prevention, and therapy of lifestyle-related disorders ●

Basic and clinical studies of metabolic syndrome ●

Basic and clinical studies of diabetes mellitus ●

Basic and clinical studies of hypertension ●

Basic and clinical studies of obesity ●

Basic and clinical studies of endocrine disorders ●

Basic and clinical studies of bone metabolic disorders ●

Basic and clinical studies of cardiovascular, renal, and cerebrovascular complications in ●

lifestyle-related disorders

Basic and clinical studies of cardiovascular endocrinology and metabolism ●

Regenerative medicine of lifestyle-relted disorders ●

Cardiovascular Medicine Takeshi KIMURA

Development study of diagnostic and therapeutic methods for ischemic heart diseases ●

Basic and clinical studies of prevention of cardiovascular diseases (Mainly, gene ●

diagnosis)

Basic and clinical studies of arrhythmia ●

Basic and clinical studies of development and progression of arteriosclerotic diseases ●

Basic and clinical studies of prevention and therapy of aneurysm ●

Development study of gene therapy and cell therapy for cardiovascular diseases ●

Basic and clinical studies of pathology of heart failure ●

Basic and clinical studies of cardiac sudden death ●

Basic and clinical studies of cause, diagnosis, and therapy of cardiomyopathy ●

Basic and clinical studies of hypertension ●

Study of pathological progression of renal disorders ●

Clinical study of interventional cardiology ●

Gastroenterology and Hepatology

Tsutomu CHIBA

Molecular biological study of cancers of digestive organs (including liver cancer) ●

Immunological, molecular biological, and clinical studies of viral hepatitis and autoimmune ●

diseases of the liver, biliary tract, and pancreas

Immunological and molecular biological study of inflammatory intestinal diseases ●

Molecular biological study of differentiation and regeneration of the intestinal tract and ●

liver

Clinical study of endoscopic therapy ●

Basic and clinical studies of liver circulation ●

Imaging diagnosis and medical therapy of liver cancer ●

Respiratory Medicine Michiaki MISHIMA

Pathogenesis, pathophysiology, diagnosis and treatment of airway diseases (COPD, ●

asthma, and chronic cough)

Multi-disciplinary investigation, diagnosis and management (including non-invasive ●

ventilation) of respiratory failure and sleep apnea syndrome

Clinical studies, diagnosis and management of lung cancer ●

Basic and clinical studies and management of interstitial lung diseases ●

Bacteriology, pathophysiology and treatment of respiratory infections ●

Rheumatology and Clinical Immunology

Tsuneyo MIMORI

Basic and clinical studies of rheumatic and connective tissue diseases ●

Basic and cliniccal studies of allergic diseases ●

Molecular pathophysiology of autoimmunity ●

Autoantibody production mechanism ●

Clinical and pathogenic significance of autoantibodies ●

Geriatric Medicine

Basic and clinical studies of development mechanism of aging-related arteriosclerosis ●

Study of comprehensive geriatric assessment ●

Study of osteoporosis ●

Basic and clinical studies of dementia and memory ●

Basic and clinical studies of ageing ●

Clinical Medicine (Core Departments)



Diabetes and Clinical Nutrition Nobuya INAGAKI

Study of insulin secretion ●

Study of glucose, lipid, and protein homeostasis ●

Study of metabolism in beta-cell and liver ●

Development of beta-cell imaging ●

Pathophysiological and genetic studies of diabetes mellitus ●

Study of diabetic complications ●

Study of secretion and action of incretin ●

Clinical study of diabetes mellitus and nutritional disorders ●

Primary Care and Emergency Medicine

Kaoru KOIKE

Study of primary care medicine ●

Study of emergency medicine ●

Basic and clinical studies of shock ●

Basic and clinical studies of sepsis ●

Nephrology

Study of optimal apheresis therapy for various diseases ●

Clinical study of indication of hemodialysis and peritoneal dialysis for ESRD ●

Study of the mechanism of onset and progression of diabetic nephropathy ●

Study of factors affecting the generation and development of the kidney ●

Study of the metabolism of drugs in the kidney ●

Dermatology Yoshiki MIYACHI

Study of immune and allergic skin diseases ●

Study of inflammatory skin diseases ●

Study of ultraviolet light biology ●

Cell biological study of skin diseases ●

Molecular biological study of skin diseases ●

Study of skin regeneration medicine ●

Pediatrics Toshio HEIKE

Study of development and regeneration of organs and tissues ●

Study of congenital metabolic abnormality ●

Study of allergic diseases in children ●

Study of immunological diseases in children ●

Study of pediatric neurology and muscular disorders ●

Study of pediatric heart diseases ●

Study of pediatric blood disorders and tumors ●

Study of neonatal diseases ●

Radiation Oncology and Image-Applied Therapy

Masahiro HIRAOKA

Systematization from diagnosis to therapy of cancer ●

Development of fourth dimensional radiotherapy ●

Development of image-guided radiation therapy ●

Development of molecular target drugs with radiosensitizing effects ●

Molecular biology and molecular imaging of hypoxic cancer cells ●

Diagnostic Imaging and Nuclear Medicine

Kaori TOGASHI

Development of new diagnostic imaging methods with MRI, CT, PET, US, RI, etc for all ●

human body regions and organs

Application of imaging modalities to image-guided therapeutics ●

Computer-aided diagnosis and related image processing ●

Development of new imaging methods and modalities in cooperation with school of ●

engineering and corporations

Basic research on the medical image ●

Clinical Laboratory Medicine Satoshi ICHIYAMA

Study of laboratory diagnostics of infectious diseases ●

Study of infection control and therapeutics ●

Study of electrocardiographic diagnostics ●

Study of neurophysiological test diagnostics ●

Gastrointestinal Surgery Yoshiharu SAKAI

Molecular biological analysis of gastrointestinal cancers ●

Study of gastrointestinal physiology ●

Study of surgical anatomy ●

Development of surgical instruments ●

Clinical study of gastrointestinal cancers ●


Research Field List


Hepatopancreatobiliary Surgery and Transplantation

Shinji UEMOTO

• Study of pancreatic cancer and its precursors ●

• Study of nutrition and ERAS (enhanced recovery after surgery) ●

• Study of genesis/regeneration of the pancreas ●

• Study of angiogenesis and hepato-biliary-pancreatic disease ●

• Study of pancreatic islet transplantation ●

• Study of development of engineered liver grafts ●

• Study of regeneration of the liver ●

• Study of organ preservation and chimera for liver transplantation ●

• Study of immune tolerance after liver transplantation ●

• Study of hepato-biliary oncology ●

• Study of hepato-biliary fibrosis ●

• Study of pediatric surgery ●

Breast Surgery Masakazu TOI

Breast cancer stem cell and adipose stem cell study ●

Development of a novel and less invasive therapy ●

Biomarker study for optimizing systemic and local therapy ●

Clinical development and application of bio-optical devices ●

Study of treatment algorithms for breast cancer patients ●

Anesthesia Kazuhiko FUKUDA

Study of surgical stress and biological reaction ●

Study of circulatory physiology and pharmacology related to surgery and anesthesia ●

Study of neurophysiology and pharmacology related to pain and pain relief ●

Molecular biological study of anesthesia and related drugs ●

Study of platelet function related to surgery and anesthesia ●

Study of hypoxic responses in anesthesia and intensive care ●

Gynecology and Obstetrics Ikuo KONISHI

Study of reproductive and developmental medicine ●

Study of infertility therapy ●

Study of malignant ovarian tumor ●

Study of uterine tumor ●

Study of endometoriosis ●

Study of perinatal medicine ●

Study of fetal medicine ●

Study of reproductive endocrinology ●

Study of reproductive immunology ●

Urology Osamu OGAWA

Study of urogenital tumors ●

Study of male reproductive system ●

Study of renal replacement therapy ●

Study of bladder pathophysiology ●

Study on regeneration of urogenital tissues ●

Cardiovascular Surgery Ryuzo SAKATA

Study of heart transplantation and assist circulation ●

Study of myocardial regeneration ●

Study of surigical ventricular restoration ●

Study of therapeutic angiogenesis for limb ischemia ●

Study of new myocardial protection ●

Development of novel devices for endovascular surgery ●

Thoracic Surgery Hiroshi DATE

Thoracic surgery ●

Lung cancer, mediastinal tumor, and chest wall tumor ●

Lung transplantation ●

Study of regeneration medicine of respiratory organs ●

Gene therapy for lung cancer ●

Plastic and Reconstructive Surgery

Shigehiko SUZUKI

Study of regeneration of skin and subcutaneous tissues ●

Study of wound healing, scar and keloid ●

Study of biomaterials ●

Study of regeneration of cartilage, bone, and nerve ●

Study of skin microcirculation ●

Study of cleft lip and palate, and other congenital deformities ●




Ophthalmology and Visual Sciences

Nagahisa YOSHIMURA

Study of age-related macular degeneration (AMD) ●

Study of diabetic retinopathy ●

Study of glaucoma ●

Study of retinal microcirculation ●

Study of regeneration of retina and optic nerve ●

Study of ocular fundus imaging ●

Study of adaptive optics scanning laser ophthalmoscopy (AO-SLO) ●

Study of genome association in AMD and high myopia/degenerative myopia ●

Otolaryngology-Head and Neck Surgery

Juichi ITO

Study of regeneration of inner ear hair cells ●

Study of speech cognition and expression mechanism ●

Study of regulation of body equilibrium ●

Study of ventilation physiology of middle ear ●

Molecular biological study of malignant tumors of the head and neck ●

Study of laryngeal pathophysiology ●

Study of regeneration of aerodygestive tract ●

Orthopaedic and Musculoskeletal Surgery

Takashi NAKAMURA

Study of artificial bone and joint materialsStudy of bone and cartilage development ●

Study of bone and cartilage metabolism ●

Study of bone and soft tissue tumors ●

Study of spinal surgery ●

Study of osteoarthritis and rheumatoid arthritis ●

Study of hand surgery and peripheral nerve regeneration ●

Study of regenerative medicine of musculoskeletal system ●

Oral and Maxillofacial Surgery Kazuhisa BESSHO

Study of hard tissue regeneration ●

Molecular biological study of tooth regeneration ●

Study of artificial tooth root and periodontal tissue regeneration ●

Study of orthognathic surgery of jaw deformity ●

Study of craniomaxillofacial development ●

Molecular biological study of jaw and oral cavity disorders ●

Mastication and higher brain function ●

Study of kinetics of oral microbial flora ●

Clinical Molecular Biology Jun FUJITA

Molecular biological study of reproductive cell differentiation ●

Molecular mechanism of liver cancer development and development of therapeutic ●

method

Study of stress response ●

Neurology Ryosuke TAKAHASHI

Study of development mechanism and therapy of extrapyramidal tract disorders including ●

Parkinson disease

Study of pathogenesis and therapy of neurodegenerative disorders including amyotrophic ●

lateral sclerosis

Study of development mechanism and therapy of Alzheimer disease and related dimentia ●

Study of diagnosis and therapy of intractable partial epilepsy ●

Study of cerebral vascular disorder and cerebral circulation/metabolism ●

Electrophysiological and pathological study of muscular and peripheral nervous diseases ●

Neurosurgery Susumu MIYAMOTO

Study of cerebrovascular disorders ●

Study of brain tumors ●

Study of functional brain neurosurgery ●

Study of neural regeneration and neuroplasticity ●

Study of intravascular surgery ●

Study of vascular metabolic function ●

Electrophysiological study of the central nervous system ●

Gene therapy for cerebrovascular disorder and brain tumors ●

Viral therapy for brain tumors ●

Study of pituitary gland generation ●

Psychiatry Toshiya MURAI

Neuroimaging ●

Psychopathology ●

Neuropsychology ●

Child and adolescent psychiatry ●

Forensic psychiatry ●


Research Field List


Transfusion Medicine and Cell Therapy

Taira MAEKAWA

Development of novel medical test methods of anti-HLA antobody for supporting cell ●

therapy and organ transplantation

Development of cell processing technology for advanced cellular therapy and regenerative ●

medicine

Study for controlling acute GVHD of hematopoietic stem cell transplantation using ●

meschenchymal stem cells

Development of cancer molecular targeting therapy ●

Study of transcriptional regulations for normal and malignant hematopoietic stem cells ●

Research for cell lineage of immature myeloid cells ●

Diagnostic Pathology Hironori HAGA

Pathological diagnostics (surgical pathology) and cytodiagnosis ●

Clinicopathological study using surgical pathological materials ●

Application of immunohistochemistry to pathology ●

Computerization of pathological diagnostic tasks ●

Medical Informatics Hiroyuki YOSHIHARA

Electronic Health Record System and Personal Health Record System ●

Hospital information system and clinical imaging system ●

Virtual Reality (VR) system for medical use ●

Natural language processing technology for medical knowledge ●

Pharmacy

Basics and clinics of pharmacokinetics, pharmacological effects, and toxicity of drugs ●

Study of molecular mechanism and clinical application of drug transporters ●

Study of variation of pharmacokinetics and pharmacological effects in pathological states ●

and individual dosing design

Elucidation of drug transporters, genetic polymorphism of metabolic enzymes, and ●

individual variation and application to tailor-made medical care

Experimental Therapeutics Akira SHIMIZUExploratory study of development of novel medical careDevelopment of medical care ●

based on analysis of genomic structure and gene expression

Clinical Trial Design and Management

Methodology for clinical development of novel medical products ●

Design, data management, statistical analysis, and interpretation for clinical studies ●

Researches on statistical analysis methods ●

Clinical Innovative Medicine Masayuki YOKODE

Development of holistic medical system for advanced therapeutics and diagnosis ●

Study of cooperative medical care by various job types for practice of novel therapeutics ●

and diagnosis

Study of comprehensive support system for the patients undergoing novel therapies and ●

diagnosis

Study of development of exploring therapy for atherosclerotic disorders ●

Study of psychological and somatic care for the patients with intractable diseases ●

including cancer

Brain Pathophysiology / Functional Brain Imaging(Human Brain Research Center)

Hidenao FUKUYAMA

Non-invasive study of movement control by the central nervous system and its disorders ●

in humans

Non-invasive study of cognitive and memorizing functions and its disorders in humans ●

Clinicophysiological study of neurological disorders ●

Study of higher function of human brain by imaging of brain function ●

Analysis of neurotransmitters by imaging of brain function ●

Development of new noninvasive brain imaging devices for noninvasive brain ●

Organ Preservation Technology(Contributed Chairs)

Researches on preservation of organs, tissues, and cells ●

Development of new preservation technologies ●

Multidisciplinary Cancer Treatment(Contributed Chairs)

Respiratory Care and Sleep Control Medicine(Contributed Chairs)

Kazuo CHIN (Hwa Boo JIN)

Study of causes, prevention, and therapy of respiratory failure ●

Basic and clinical studies of sleep medicine ●

Basic and clinical studies of sleep disordered breathing ●

Clinical studies of respiratory care ●

Basic and clinical studies of sustained and intermittent hypoxemia ●

Translational Clinical Oncology(Contributed Chairs)

Clinical study of cancer chemotherapy ●

Clinical study of supportive care medicine in cancer chemotherapy ●

Pharmacogenetic study of cancer chemotherapy ●

Molecular pathology of human cancer ●




Ghrelin Research Project Takashi AKAMIZU Exploratory study for new drug development of Ghrelin ●

Lactosome Project Shunsaku KIMURA

Exploratory study for molecular imaging probe on cancer ●

Exploratory study for nanocarrier on drug delivery system ●

Exploratory study on diagnostic and therapeutic agents ●


Epidemiology and Healthcare Research

Shunichi FUKUHARA

Measurement and analysis of quality of care and outcomes ●

Quantitative evaluation of diagnostic measures ●

Study on clinical reasoning ●

Pharmacoepidemiology Koji KAWAKAMI

Researches on new drug approval and regulatory systems ●

Reseaches on clinical trials ●

Drug safety researches including pharmacoepidemiology and pharmacoeconomics ●


Hybrid peptide therapiy researches focusing cancer and inflammatory diseases ●

Healthcare Economics and Quality Management

Yuichi IMANAKA

Policy and economics of health care ●

Management of healthcare organizations ●

Healthcare reform in policy and system ●

Quality, safety, efficiency and equity of health care and its improvement ●

Costing, pricing and performance measurement in health care ●

Medical Ethics Shinji KOSUGI

Study of ethical examination ●

Study of medical care for heredity ●

Study of medical care policy ●

Health and Environmental Sciences

Akio KOIZUMI

Genetic epidemiology of lifestyle disorders ●

Risk evaluation of Persistent Organic Pollutants ●

Genetic epidemiology of preventable multifactorial diseases ●

Industrial toxicology ●

Global Health and Socio-epidemiology

Masahiro KIHARA Socio-epidemiological study of prevention of HIV infection ●


Department of Radiation System Biology (Laboratory of Genome Maintenance)

Tomohiro MATSUMOTO

Radiation response of cell cycle ●

Genomic stability and carcinogenesis ●

Department of Mutagenesis (Division of Chromatin Regulatory Network)

Study of mechanism of muatagenesis ●

Study of DNA radiation injury repair system ●

Study of biological rhythm control by light ●

Department of Late Effect Studies (Laboratory of DNA Damage Signaling)

Minoru TAKATA

Mechanisms of genetic instability in cancer ●

Signal transduction mechanisms in DNA damage response ●

Molecular pathogenesis of Fanconia anemia and related medical conditions ●

Department of Genome Dynamics (Laboratory of Genome Dynamics)

Kenshi KOMATSU

DNA recombination and cell cycle control ●

Chromosomal instability-associated human hereditary diseases and genomic dynamics ●

Intracellular network of various DNA repair proteins ●


Chemical Biology Motonari UESUGI

Discovery and design of small molecule tools for cell biology and cell therapy ●

Cell biology empowered by small molecules ●

Small molecule-based bioimaging ●

Social Medicine

Radiation Biology Center

Institute for Chemical Research

Translational Research Center


Research Field List


Molecular and Cellular BiologyStudy of quality control mechanism in mammalian cells ●

Cell biological study of molecular chaperones ●

Ultrastructural ResearchStudy of general transcription regulatory system ●

Study of basics and application of RNA aptamer ●

Experimental Pathology Shimon SAKAGUCHI

Cell biological study of molecular basis of introduction and maintenance of immune ●

tolerance

Study of cause and development mechanism of autoimmune diseases ●

Study of tumor immunity induction mechanism and transplantation immune tolerance ●

mechanism

Study of cause and development mechanism of rheumatoid arthritis ●

Immunobiology and Hematology Takashi NAGASAWA

Action mechanism of chemokines in development and immune response ●

Molecular control system of development of blood and immune system cells ●

Molecular basis of microenvironments in organs supporting stem and progenitor cells ●

Organ-specific molecular mechanism of angiogenesis ●

Cellular Differentiation Yuji HIRAKIStudy of molecular mechanism of osteogenesis and chondrogenesis ●

Study of anti-angiogenic barriers in mesenchymal tissues ●

Development and Differentiation Norio NAKATSUJI

Study of development and differentiation of germ lineage cells ●

Developmental engineering research using mouse ES cell lines ●

Derivation and basic research of human ES cell lines ●

Application of ES/iPS cell lines for disease models and drug discovery research ●

Growth RegulationAtsuko SEHARA-FUJISAWA

Intercellular interaciton in morphogenesis ●

Study of cell proliferation and differentiation control mechanism in development and ●

regeneration

Study of tissue construction mechanism ●

ImmunologyStudy of thymus, thymic lymphoma and T cell differentiation ●

Study of T cell receptor gene rearrangement ●

Tissue Regeneration Junya TOGUCHIDA

Study of proliferation and differentiation of mesenchymal cells ●

Study of transformation of mesenchymal cells ●

Regenerative medicine of mesenchymal tissues ●

Organ Reconstruction

Development of regeneration medicine for metabolic disorders ●

Development of pancreatic islet regeneration therapy for diabetes ●

Induciton of stem cell differentiation to pancreatic islet, nerve, liver, and cardiac muscle ●

Development of regeneration medicine using encapsulated cells and/or tissues ●

Bioartificial Organs

Study of tissue engineering ●

Study of diagnosis and therapeutics by medical engineering ●

Development study of reconstructive surgery and artificial organs ●

Nano Bioprocesses Akihiro KUSUMI

Developing single-molecule imaging/manipulation technology, applicable to living cells ●

Elucidating signal transduction mechanisms in/on the plasma membrane, including ●

GPCRs, receptor-type tyrosine kinases, raft-associated receptors, with a special attention paid to nano-meso membrane domains and multiple-molecular complexes

Elucidating neuronal activity-dependent formation and modulation mechanisms of ●

neuronal circuits

Elucidating the interactions between the plasma membrane and the cytoskeleton ●

Medical Simulation Engineering

Study of simulation medical engineering ●

Study of biomechanics ●

Study of medical materials ●

Study of medical system engineering ●

Institute for Frontier Medical Sciences



Gene Analysis Yoshinori AKIYAMA

Study of protein dynamics in bacterial cell surface ●

Biological study of human immunodeficiency virus ●

Study of carcinogenesis inhibitors and promoters at the molecular level ●

Biological study of human papillomavirus ●

Molecular biology of Wnt signal transmission pathway ●

Cell Regulation Masahiko SUGITA

A paradigm for lipid-specific immune responses in disease ●

Lipid biology of microbes and cancer cells ●

Vaccine development against human tuberculosis and AIDS ●

Laboratory of Human Tumor Viruses

Keizo TOMONAGA

Molecular mechanism of bornavirus pathogenesis and replication ●

Molecular biological analysis of influenza virus infection ●

Development of RNA virus vectors ●

Molecular biological study of hepatitis C virus ●

Molecular biological study of proliferation control of hepatitis C virus-infected cells ●

Laboratory of Biological Protection

Koichi IKUTA

Epigenetic control of lymphocyte antigen receptor genes ●

Role of cytokine receptor in differentiation and maintenance of lymphocytes ●

Control of cytokine receptor gene expression during immune development and response ●

Imaging and in vivo function of immune microenvironment ●

Laboratory of Infection and Prevention

Molecular biology of immune allergic diseases ●

Molecular biology of thioredoxin family ●

Study of stress signals and redox regulation ●

Molecular mechanism of carcinogenesis and hyperlipidemia ●

Laboratory of Growth Regulation Ryoichiro KAGEYAMA

Molecular mechanism of differentiation, development, and regeneration of neurons ●

Gene expression control system of the nervous system ●

Study of biological clocks controlling development ●

Pathogenesis Yoshio KOYANAGI

Molecular biological study of retrovirus replication mechanism ●

Elucidative study of pathogenicity of HIV ●

Basic study for gene therapy ●

Viral Infections Masao MATSUOKA

Molecular mechanism of human T cell leukemia virus associated pathogenesis ●

Development of therapeutic strategy to HTLV-1 associated diseases ●

Development of new anti-HIV-1 drugs, and mechanism of resistant viruses ●

Viral Pathogenicity Tatsuhiko IGARASHI

Molecular biological study of pathogenicity and leukemogenicty of AIDS and ATL viruses ●

Molecular immunological and molecular genetic study of origin, evolution, and mutation of ●

AIDS and ATL viruses

Immunological study of infection and disease development mechanisms of AIDS and ATL ●

viruses and basic sutdy for vaccine development


Radiation Biology Masami WATANABECellular and molecular mechanism of radiation carcinogenesis ●

Molecular mechanism of stress response ●

Particle Radiation Oncology Koji ONO Study of diagnosis and therapy using radiation (particle beam) ●


Pathogenic Microbiology Mitsuaki NISHIBUCHI

Distribution of bacterial and other pathogens in Asian and tropical environments ●

Epidemiology, diagnosis, and prevention of the infections by bacterial and other ●

pathogens in Asian and tropical environments

Association of the features of Asian and tropical environments with the trend of infections ●

by bacterial and other pathogens in these environments

Field Medicine Kozo MATSUBAYASHI

Field Medica Study on Community-Dwelling Elderly in Japan ●

Field Medica Study on Community-Dwelling Elderly in Asia and Africa ●

Study on Neurodegenerative Diseases in New Guinea ●

Research Reactor Institute

Center for Southeast Asian Studies

Institute for Virus Research


Research Field List


Reprogramming Regulation Field Shinya Yamanaka

Functional analysis and discovery of reprogramming factors. ●

Gene expression analysis during direct reprogramming. ●

Evaluation of safeness of induced Pluripotent Stem cells. ●

Establishment of the efficient method for iPS cell generation. ●

Differentiation Induction Field Junya Toguchida

Study of molecular mechanisms of differentiation from induced pluripotent stem (iPS) ●

cells into various tissue-specific cells including mesenchymal cells, caridovascular cells, cells of central nervous systems, and cells of kidney and liver

Establishment of highly efficient and safe methods to induce differentiation ●

Disease modeling with patient-derived iPS cells

Tatsutoshi Nakahata

Establishment of disease-specific iPS cells ●

Pathophysiological study of various diseases such as the congenital diseases including ●

hematological disorders with bone marrow failure, primary immunodeficiency diseases, refractory pediatric neurological diseases, and congenital hearing loss using iPS cells

Development of new drugs and cell therapies using iPS cells ●


Develpomental Biology Takashi HIIRAGI

Systems-level understanding of early mammalian development ●

Molecular mechanism of polarity establishment in the mouse embryo ●

Centrosome inheritance and transition from meiosis to mitosis ●

Cellular polarity establishment ●

Developmental clock ●


Medical Embryology (RIKEN Center for Developmental Biology)

Yoshiki SASAI

Study of molecular mechanism of early central nervous development ●

In vitro study of nerve differentiation control ●

Study of regeneration medical application of nerve differentiation control ●

Molecular biological study of pattern formation in early embryo ●

Reproductive Biotechnology (RIKEN Center for Developmental Biology)

Teruhiko WAKAYAMAStudy of somatic cell nuclear reprogramming ●

Study of mammalian fertilization ●

Developmental Biology (Osaka Bioscience Institute)

Takahisa FURUKAWA

Molecular mechanisms of synapse formation in the retina and brain ●

Molecular mechanisms of primary cilia formation and function in the CNS ●

Mechanisms of cell fate determination of the vertebrate retina ●

Functional analysis of microRNA expressed in the retina and brain ●

Generation of KO/transgenic mice and analysis of their visual function ●

Application Biology and Regenerative Medicine(RIKEN Center for Developmental Biology)

Masayo TAKAHASHI

Research about mechanism of neural regeneration in the central nervous system ●

Transplantation research of ES/iPS-derived cells ●

Genetic analysis and pathology research of retinal degenerative diseases ●

Institute for Integrated Cell-Material Scienses (iCeMS)

Affiliate Graduate School

Center for iPS Cell Research and Application (CiRA)



Biostatistics Tosiya SATO

Epidemiologic methods ●

Clinical trials methods ●

Causal inference ●


Shunichi FUKUHARA

Measurement and analysis of quality of care and outcomes ●

Quantitative evaluation of diagnostic measures ●

Study on clinical reasoning ●

Pharmacoepidemiology Koji KAWAKAMI


Reseaches on clinical trials ●

Drug safety researches including pharmacoepidemiology and pharmacoeconomics ●


Hybrid peptide therapiy researches focusing cancer and inflammatory diseases ●

Genomic epidemiology Fumihiko MATSUDA

Identification of genetic factors related to human multifactorial diseases ●

Genetic epidemiology of community-based prospective genome cohorts ●

Development of database for the management of genomic studies ●


Yuichi IMANAKA

Policy and economics of health care ●

Management of healthcare organizations ●

Healthcare reform in policy and system ●

Quality, safety, efficiency and equity of health care and its improvement ●

Costing, pricing and performance measurement in health care ●

Medical Ethics and Medical Genetics

Shinji KOSUGI

Study of ethical examination ●

Study of medical care policy ●

Study of medical care for heredity ●

Health Informatics Takeo NAKAYAMA

Evidence-based healthcare ●

Health informatics and communication ●

Narrative and patient experiences ●

Medical Communication

Interaction between medicine and society ●

Sociological analysis of medicine ●

Communication among health professionals ●

Management of Technology and Intellectual Property

Hirokazu YAMAMOTOStudy of management of intellectual property in medical science area ●

Study of technology transfer ●


Akio KOIZUMI

Genetic epidemiology of lifestyle disorders ●

Risk evaluation of Persistent Organic Pollutants ●

Genetic epidemiology of preventable multifactorial diseases ●

Industrial toxicology ●

Health Promotion and Human Behavior

Toshiaki FURUKAWA

Behavioral medicine ●

Cognitive-behavior therapy of mood and anxiety disorders ●

Evidence-based mental health ●

Clinical epidemiology ●

Preventive Services Takashi KAWAMURAEpidemiological analysis of disease development process ●

Development of preventive medical care ●


Masahiro KIHARA

Epidemiology of HIV/AIDS&STD ●

Behavioral epidemiology of high risk populations for HIV infection ●

Socio-epidemiological study of prevention of HIV infection ●

Public Health and International Health

Toshitaka NAKAHARA

Study of health policy ●

Study of international health ●

Study of health promotion and health education ●

Ecology with Emphasis on the Environment (Center for Southeast Asian Studies)

Mitsuaki NISHIBUCHI

Incidence and spread of infectious diseases in humans in Asia and developing countries ●

Environmental factors responsible for infectious diseases in humans in Asia and ●

developing countries

Association between incidence and spread of infectious diseases in humans with ●

environmental factors in Asia and developing countries

Field Medicine (Center for Southeast Asian Studies)

Kozo MATSUBAYASHI

Field Medica Study on Community-Dwelling Elderly in Japan ●

Field Medica Study on Community-Dwelling Elderly in Asia and Africa ●

Study on Neurodegenerative Diseases in New Guinea ●

Public Health (Professional Degree Program / Doctoral Program)


Research Field List


Environmental Health Nursing Sawako SUGAStudy of living environment in nursing ●

Study of nursing counseling ●

Human Body Defense & Patho-physiology Nursing Science

Yumi SAITOShinichi NOMOTO

Study of infection control nursing ●

Study of stress reduction for immuno compromised host ●

Development on the ubiquitous system for community health care ●

Reserch on liveable cities on the creation of urban health sciences ●

Nursing Science for Lifestyle-Related Diseases

Kiminori HOSODAKazuko NIN

Study of nursing science for Lifestyle-Related Diseases ●

Study of Lifestyle-Related Diseases ●

Psychiatric Nursing Shigeru SAKURABA

Study of Pothography ●

Study of child and adolscent psychiatry ●

Study of researches on suicide nurcing ●

Study of development of new diagnostic imaging methods with NIRS,EEG ,etc for the ●

brain function

Study of support for families of children with development disabilities ●

Study of the support for social independence of mentally handicapped people at sheltered ●

workshops

Study of development of the cooperation system model for pregnant women with ●

psychiatric disorder

Critical Care Nursing

Study of critical care patients ●

Study of organ transplantation nursing care ●

Study of sense of coherence around critical care ●

Child Health and Development Nursing

Machiko SUZUKI Study of nursing of medically dependent children and their families ●

Midwifery and Women's Health Kiyoko KABEYAMA

Longitudinal study on labor pain intensity and related factors ●

Study of pregnant/postpartum women who underwent fertility treatment and their partners ●

Developments of fetus phantoms and the educational guideline for ultrasound scan in the ●

midwifery diagnosis

Study of women’s health assessed by autonomic nervous system activity and infrared ●

thermography

Study of reproductive health/rights ●

Research on the international comparison of midwifery education ●

Female Life-Cycle Nursing Nobuhiko SUGANUMA Reproducive Medicine Infertility Obstetrics and Gynecology Sexology ●

Preventive Nursing Toshiki KATSURA

Cohort Study on prevention of lifestyle-related diseases and health behaviors ●

Study on successful aging and health promotion in a community ●

Study on building a healthy and safety town ●

Administrative study on health promotion strategy and community diagnosis ●

Study on prevention of falls of the erderly people ●

Home Healthcare Nursing Ayae KINOSHITA

Study of pathogenesis of Alzheimer's disease ●

Development of IT-based home health care system ●

Analytical study of the stress of dementia patients' caregivers ●

Human Health Science (Master / Doctoral Program)

Nursing Science



Basic Laboratory ScienceShogo OKAKuniaki SAITO

Study of biological information inherent in sugar chains ●

Innovational Laboratory Medicine Tetsuya TAKAKUWA Study of human embryo using MR imaging ●

Applied Laboratory ScienceSouichi ADACHIAkihiko NAKAIZUMIMasatoshi FUJITA

Mechanisms of new type of cell death induced by molecular target therapy ●

Development of new treatments and new prognostic factors in child AML ●

Early diagnosis of pancreatobiliary malignancies ●

Conventional or rapid cytological examinations in digestive malignancies ●

Development of acceleration bed for improving QOL of elderly ●

Medical Devices for Diagnoses Akitoshi SEIYAMA

Development of new quantitative neuroimaging techniques (Neurocalorimetry) ●

Developments of BMI technology based on EEG and NIRS ●

In vivo molecular imaging (BioSeeThrough Project) ●

Analyses of biosignals for understanding brain function ●

Innovative Medical Imaging Technology

Naozo SUGIMOTO

Development of imaging and image processing methods for quantitative analysis of multi ●

dimensional medical images including multi modality images or sequential images

Development of various medical applications such as computer aided diagnosis or ●

therapy system by using the above methods

Development of MR microscopy system (hardware and software) ●

Medical Imaging System Sciences

Tsuyoshi SHIINA

Basic theory of non-invasive sensing and imaging of biomedical information ●

Development of novel medical modalities for diagnosis and minimally-invasive treatment ●

support

Advanced ultrasound and optical imaging technology and its clinical application ●

Medical image processing and computer-aided-diagnosis ●


Motor Function AnalysisHiroshi KUROKIMakoto ISHIBASHI

Molecular mechanisms of morphogenesis during development of the central nervous ●

system, limb and cartilage

Study on rehabilitation for articuloar cartilage and knee osteoarthritis ●

Development and Rehabilitation of Motor Funcition

Noriaki ICHIHASHITadao TSUBOYAMA

Study of biomechanics and motor control of human movement ●

Clinical study on musculoskeletal disorders ●

Analysis of muscle function ●

Study on interventions for preventing falls in elderly ●

Study on rehabilitation for cancer patients ●

Clinical Cognitive NeuroscienceToshiko FUTAKIMotomi TOICHIAkira MITANI

Rehabilitation on occupational behavior in functional disorder ●

Electrophysiological and neuroimaging study on cognition in psychiatric disorders ●

Neuroscience-based rehabilitation ●

Brain Function and Rehabilitation

Hiroshi YAMANEOccupational therapy for mental disorders ●

Group dynamics and communication ●


Innovation Unit for Near Future System and Technology

Hidenori ARAI

Prevention of falls ●

Prevention of the decline of ADL in frail elderly ●

Research on the effect of discharge planning on QOL of a patient and their family and on ●

the education tools for medical staffs

Effect of comprehensive geriatric assessment (CGA) during hospitalization on ADL and ●

QOL after discharge

Rehabilitation Sciences

Fusion Unit for Near Future Human Health Sciences

Laboratory Science


Brain is the largest frontier in the biological research. Our laboratory has made a significant progress in brain research by using various research tools. To make further progress and explore the new horizon in this field, power of flexible imagination of young people is indispensable. We welcome young students to our laboratory and hope them working together to create new aspects in brain research.

Dai Watanabe, M.D., Ph.DProfessor

Research and EducationThroughout recorded time, the human brain - a spongy, 1.5 kilogram mass of fatty tissue - has been compared to a telephone switchboard and a supercomputer.But the brain is much more complicated than any of these devices, a fact scientists confirm almost daily with each new discovery. The extent of brain's capabilities is unknown, but it is the most complex living structure known in the universe.This single organ controls all body activities, ranging from heart rate and sexual function to emotion, learning and memory. The brain is even thought to influence the response to disease of the immune system and to determine, in part, how well people respond to medical treatments. Ultimately, it shapes our thoughts, hopes, dreams and imagination. In short, the brain is what makes us human.Neuroscientists have the daunting task of deciphering the mystery of this most complex of all machines: how as many as a trillion nerve cells are produced, grow and organize themselves into effective, functionally active systems that ordinarily remain in working order throughout a person's lifetime.Our laboratory has made a significant contribution in understanding brain function by utilizing numbers of up-to-date techniques such as molecular cloning, electrophysiology, gene manipulation of living animals, behavioral analysis and gene profiling.

Recent Publications1. Watanabe D, Nakanishi S.(2003) mGluR2 postsynaptically senses granule cell inputs at Golgi cell

synapses. Neuron;39(5):821-829 2. Yamamoto M, Wada N, Kitabatake Y, Watanabe D, Anzai M, Yokoyama M, Teranishi Y,

Nakanishi S.(2003) Reversible suppression of glutamatergic neurotransmission of cerebellar granule cells in vivo by genetically manipulated expression of tetanus neurotoxin light chain. J. Neurosci.;23(17):6759-6767.

3. Soda T, Nakashima R, Watanabe D, Nakajima K, Pastan I, Nakanishi S.(2003) Segregation and coactivation of developing neocortical layer 1 neurons. J. Neurosci.;23(15):6272-6279.

❶ Cajal-etzius cells in naonatal cerebral cortex.

Important in organized cortex development.

❷ An Amacrine cell in retina. Essent ia l for v isual in formaton

procesing.❸ Glutamate receptor in Hippocampus. Center of learning and memory

formation.❹ Staffs

Biological SciencesProfessor : Dai Watanabe Associate Professor : Yoshiaki Nakajima TEL : +81-75-753-4437 FAX : +81-75-753-4404 e-mail : [email protected] URL : http://www.phy.med.kyoto-u.ac.jp/

Biological Sciences

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- Basic Medicine (Core Departments) - Biological Sciences


Vertebrate body has quite complex structures, which are generated by the process called “morphogenesis”. The mechanism of morphogenesis is still not well understood even in this post-genome era. Alternative splicing of pre-mRNA generates a highly dynamic human proteome through networks of coordinated splicing events, and is regulated on tissu-specific stage-dependent way.Our goal is to establish a new paradigm on the mechanism of morphogenesis from the view point of mRNA processing regulation. We will also try to find chemical modifiers of mRNA splicing, which will be applicable for clinical therapy against malignant tumors, virus infections and neuromuscular diseases caused by aberrant splicing. We welcome enthusiastic young researchers who will challenge to open new fields of biology.

Masatoshi HagiwaraProfessor

Research and Education1)Decipherment of splicing codeRecent whole genome sequence analyses revealed that a high degree of proteomic complexity is achieved with a limited number of genes. This surprising finding underscores the importance of alternative splicing, through which a single gene can generate structurally and functionally distinct protein isoforms. Alternative splicing events are dynamically regulated in developmental stage-dependent and tissue specific manners. Pre-mRNAs contain a ‘splicing code’ made up of loosely defined consensus sequences that define the splice junctions and a bewildering number and diversity of relatively short cis-acting elements within exons as well as introns. To decipher the splicing code, we have developed transgenic alternative splicing reporter systems that enable us to visualize alternative splicing events in living nematode. With this reporter system, we have identified trans-acting factors and cis-elements involved in the splicing regulation and found some evolutionally conserved regulation mechanisms of alternative splicing.We recently developed transgenic reporter mice that enable us to visualize dynamic alternative splicing events in single cell resolution.2) Development of new drugs to cure RNA diseasesThere is a growing awareness that misregulations of mRNA processing are causative of many human diseases including hereditary, inflammatory and tumorigenic diseases. Thus new therapeutic approaches that target RNA processing mechanisms are highly anticipated. We focused on the mRNA splicing process, and have developed compounds that alter the alternative splicing events or even reverse some misregulated splicing events. Using splicing reporter systems, we screen and select chemical modifiers of splicing, examine their biological function during developmental stages, and consider their applications to crure hitherto intractable diseases.3) Mathematical modeling of spontaneous pattern formation process during mammalian development.During vertebrate development, spontaneous pattern formation (formation of pattern out of seemingly homogeneous initial state) is frequently observed, such as lung branching, limb skeletogenesis and skull suture interdigitation. These processes are quite complex and we cannot understand them by simply analyzing each gene involved. We formulated mathematical models which represents essential feature of these pattern formation process, and are now trying to verify the models by developing novel experimental methods.

Recent Publications1. Ogawa Y, Nonaka Y, Goto T, Ohnishi E, Hiramatsu T, Kii I, Yoshida M , Ikura T , Onogi H ,

Shibuya H , Hosoya T, Ito N, and Hagiwara M (2010) Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. Nature Commun.1, 86, doi:10.1038/ncomms1090

2. Kuroyanagi H, Ohno G, Sakane, H, Maruoka, H, and Hagiwara M (2010) Visualization and genetic analysis of alternative splicing regulation in vivo using fluorescence reporters in transgenic Caenorhabditis elegans. Nature Protoc. 5, 1495-1517.

3. Kondo S and Miura T (2010) Reaction-diffusion model as a framework for understanding biological pattern formation. Science. 329(5999):1616-1620. Review.

4. Ohno, G., Hagiwara, M. and Kuroyanagi, H. (2008) STAR family RNA-binding protein ASD-2 regulates developmental switching of mutually exclusive alternative splicing in vivo. Genes & Dev., 22,360-374.

5. Ideue T, Sasaki Y, Hagiwara M and Hirose T. (2007) Introns play an essential role in splicing-dependent formation of the exon junction complex. Genes & Dev., 21, 1993-1998.

6. Kaida D, Motoyoshi H, Tashiro E, Nojima T, Hagiwara M, Ishigami K, Watanabe H, Kitahara T, Yoshida T, Nakajima H, Tani T, Horinouchi S and Yoshida M (2007) A novel cell cycle inhibitor spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nature Chem. Biol., 3, 576-583.

7. Miura T, Hartmann D, Kinboshi M, Komada M, Ishibashi M, Shiota K, The cyst-branch difference in developing chick lung results from a different morphogen diffusion coefficient, Mech. Dev. 126, 160-72 (2009)

Anatomy and Developmental BiologyProfessor : Masatoshi HagiwaraAssociate Professor : Takashi MiuraResearch Associate Professor : Naoyuki KataokaAssistant Professor : Akihide Takeuchi, Kensuke NinomiyaResearch Assistant Professor : Isao Kii, Yukiko OkunoTEL : +81-75-753-4341 FAX : +81-75-751-7529 e-mail : [email protected] URL : http://www.anat1dadb.med.kyoto-u.

ac.jp/Anat1DADB/TOP.html

Anatomy and Developmental Biology

- Basic Medicine (Core Departments) - Anatomical Science


The human body consists of 6 trillion cells with at least 210 distinct types. Each of these cells has its own unique character, and it is essential for human life for these cells to develop, maintain themselves, and function appropriately. The essential information code that defines a cell’s unique character is the epigenome, which refers to the whole-genome assembly of epigenetic modifications of chromatin, including DNA methylation and a variety of histone modifications. It is the states of the epigenome that determine the growth, differentiation, responses to external stimuli, aging, and diseased conditions of the cells in our body. By using all the available methodologies in life science as well as by developing new ones, we are aiming to understand the basis of epigenetic regulations and to appropriately control the growth, differentiation, and function of the cells in vitro.

Mitinori Saitou, M.D., Ph.D.Professor

Research and EducationAll of the diverse cell types in the body can be broadly classed as either somatic or germline cells. In contrast to somatic cells, which work to maintain the constant, stable form and function of an individual organism’s body, germ cells provide the faithfully replicated information needed to establish subsequent generations of individuals. In order to fulfill this role, these cells need to exhibit certain unique properties, including the ability to undergo epigenetic reprogramming, to divide meiotically, and to revert (generally through fusion with another germline cell) to a state of developmental totipotency and maintain that totipotent state until the start of ontogeny. Research in our laboratory is geared to elucidating the developmental bases of germline function at the molecular levels from the very earliest stages of germline development. Specifically, our subjects of interest are the molecular mechanisms, at the levels of both signaling and transcription, involved in the formation of mouse primordial germ cells (PGCs), the cellular progenitors of sperm and oocytes, the genome-wide epigenetic reprogramming that takes place immediately following PGC establishment, the development and application of technologies to enable the analysis of transcriptional regulatory networks at the single-cell level, and ultimately, reconstitution of germ cell development in vitro.Our studies have so far shown that germ cell specification in mice integrates three key events: repression of the somatic program, reacquisition of potential pluripotency, and genome-wide epigenetic reprogramming. We have identified a PR-domain-containing protein, Blimp1 (also known as Prdm1), as a critical factor for PGC specification. Using a highly representative single-cell microarray technology that we developed, we identified complex but highly ordered genome-wide transcription dynamics associated with PGC specification. This analysis not only demonstrated a dominant role of Blimp1 for the repression of the genes normally down-regulated in PGCs relative to their somatic neighbors, but also revealed the presence of gene expression programs initiated independently from Blimp1. Among such programs, we identified Prdm14, another PR-domain-containing protein, as a key regulator for the reacquisition of potential pluripotency and genome-wide epigenetic reprogramming. The launch of the germ cell lineage in mice, therefore, is orchestrated by two independently acquired PR domain-containing transcriptional regulators, Blimp1 and Prdm14. Furthermore, we have identified a signaling principle in germ cell fate specification. Such studies may provide fundamental information on the reconstruction of the germ cell lineage from pluripotent stem cells in vitro.

Recent Publications1. Yabuta, Y., Ohta, H., Abe, T., Kurimoro, K., Chuma, S., and Saitou, M. (2011). TDRD5 is required

for retrotransposon silencing, chromatoid body assembly and spermiogenesis in mice. The Journal of Cell Biology, in press.

2. Yamaji, M., Tanaka, T., Shigeta, M., Chuma, S., Saga, Y., and Saitou, M. (2010). Functional reconstruction of Nanos3 expression in the germ cell lineage by a novel transgenic reporter reveals distinct subcellular localizations of Nanos3. Reproduction, 139, 381-393.

3. Ohinata, Y., Ohta, H., Shigeta, M., Yamanaka, K., Wakayama, T., and Saitou, M. (2009). A signaling principle for the specification of the germ cell lineage in mice. Cell, 137, 571-584.

4. Yamaji, M., Seki, Y., Kurimoto, K., Yabuta, Y., Yuasa, M., Shigeta, M., Yamanaka, K., Ohinata, Y., and Saitou, M. (2008). Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nature Genetics, 40, 1016-1022.

5. Kurimoto, K., Yabuta, Y., Ohinata, Y., Shigeta, M., Yamanaka, K., and Saitou, M. (2008). Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes & Development, 22, 1617-1635.

❶ Expression of Blimp1 and Prdm14 in mouse embryos at embryonic day 7.0.❷ Sperm differentiated from induced primordial germ cells from the epiblasts engineered

to express GFP (left) are fertilization-competent and can be used to generate normal offspring (right; green shows GFP fluorescence)

Anatomy and Cell BiologyProfessor : Mitinori Saitou Senior Lecturer : Katsuhiko Hayashi Assistant Professor : Kazuki Kurimoto, Hiroshi Ohta TEL : +81-75-753-4335 FAX : +81-75-751-7286 e-mail : [email protected]

Anatomy and Cell Biology

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- Basic Medicine (Core Departments) - Anatomical Science


We aim at clarifying the mechanisms underlying the cardiac cell function. So far, we examined the membrane excitation, muscle contraction and their regulation on the molecular level. By implementing these experimental findings into a comprehensive computer model, a variety of cell functions have been successfully reconstructed. Our educational policy is dependent on motivation of individual students. To encourage their motivation, we spend more time in doing experiments than for surveying literature. Students from different discipline are welcome to introduce natural sciences to medical study.

Research and Education■Automaticiy of the heartThe hear t , even i f d i ssec ted out f rom the experimental animal, can continue spontaneous beat provided appropriate conditions such as ion concentrations and oxygen supply. This automaticity is due to a group of specialized muscle cells, called pacemaker cells enbedded in the right atrium. We isolate living pacemaker cells and apply the electrode to measure its electrical activity. Now the activity of pacemaker cells can be reconstructed on computer based on experimental findings.

■Energy metabolism of the heart muscle.The heart start its function to drive the blood circulation at the early stage of embryo and continue until the end of life. For the continusous heart beat, it is essential for the heart cells to receive both the nutrients and oxygen without any break. The biological energy is produced mainly by mitochondria and used by cell contraction and related processes. We also aim at reconstructing these energy metabolims on the computer model.

■Computer modeling of Cell/Biodynamics'Integration' is now our central task. We are chal lenging to organize enormous body of experimental evidence and bringing together many classical discoveries on molecular as well as system levels into a comprehensive dynamic biological models. 'Integration' using the modern computer technology will vastly change the paradigm of present scientific researh as well as industrialization process. The computerized mechanisms of biological function will reconstruct versatile responses of our body to various inputs such as variable environmental changes, physiological conditions, disease and drug administration.

Recent Publications1. Matsuoka S, Sarai N, Jo H, Noma A. Simulation of ATP Metabolism in Cardiac Excitation-

Contraction Coupling. Progress in Biophysics and Molecular Biology, 85;279-299 (2004) 2. Cho HS, Takano M, Noma A. The electrophysiological properties of spontaneously beating

pacemaker cells isolated from mouse sinoatrial node. Journal of Physiology 550;169-180 (2003) 3. Matsuoka S, Sarai N. Kuratomi S, Ono K, Noma A. Role of individual ionic current systems in

ventricular cells hypothesized by a model study. Japanese Journal of Physiology 53;105-123 (2003) 4. Kuratome S, Matsuoka S, Sarai N, Powell T, Noma A. Involvement of Ca2+ buffering and Na+/

Ca2+ exchange in the positive staircase of contraction in guinea-pig ventricular myocytes. Pflugers Archiv 446;347-355 (2003).

❶ An isolated pacemaker cell (left) and the ventricular myocyte. To the pacemaker cel, a patch electrode is attached to record its electrical activity. The vertical bars indicate 20 micro m.

❷ The composition of our computer model of a cardiac myocyte. The model can reconstruct the membrane excitation, ionic homeostasis, the contraction and the ATP homeos tas is including the mitochondria.

❸ Staffs

Physiology and BiophysicsAssociate Professor : Tamotsu Mitsuiye Associate Professor (JST) : Satoshi Matsuoka Assistant Professor : Ayako Takeuchi TEL : +81-75-753-4353 FAX : +81-75-753-4349 e-mail : [email protected] URL : http://www.card.med.kyoto-u.ac.jp/

Physiology and Biophysics

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- Basic Medicine (Core Departments) - Physiology

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The cancer death rate is increasing every year, mostly due to invasion and metastasis. Accordingly, overcoming cancer invasion and metastasis should be on top of the agenda in today's research. To this end, we will need a wide-range basic research from molecular and cellular levels, to whole body studies aiming at novel therapeutic strategies. In our laboratory, we have constructed many mouse models of gastrointestinal polyposis and cancer. Using such models, we have proven the role of cyclooxygenase 2 (COX-2) in polyp formation and established the therapeutic strategy with COX-2 inhibitors. We are currently pursuing studies focusing on mouse models of invasive and metastatic cancers. Because of years of experience in research in USA by the principal investigator, special emphasis is placed on the graduate and postdoctoral training with international views.

Makoto Mark Taketo, M.D., Ph.D.Professor

Research and EducationIn our laboratory, we have constructed many mouse tumor models, making extensive use of the transgenic and gene knockout technology. For example, we have constructed Apc-Δ(delta)716 knockout mice as a model for familial adenomatous polyposis (FAP). In this model, we discovered that COX-2 is induced at a very early stage, and contributes to the expansion of the polyps. We have also developed a mouse model of colon cancer (adenocarcinoma) that shows strong invasion. Using this model, we have recently reported that the cancer epithelium, where the TGF-β(beta) family signaling is inactivated, expresses a chemokine ligand and attracts bone marrow-derived immature myeloid cells that produce proteases and help the tumor epithelium invasion. Based on these achievements, we are currently pursuing the following research projects.

1) Identification of genes that regulate malignant progression2) Role of iMCs in colon cancer invasion and metastasis3) Analysis of signaling pathways that are essential for tumorigenesis4) Pre-clinical study for cancer therapy

In pursuing these research projects, we focus on training of young scientists in a wide variety of techniques in recombinant DNA technology, embryonic stem cell culture and homologous recombination, mouse embryo manipulation, mouse genetics, histopathology, and pharmacology as well as up-to-date knowledge in the related fields.

Recent Publications1. Sonoshita M, Aoki M, Fuwa H, Aoki K, Hosogi H, Sakai Y, Hashida H, Takabayashi A, Sasaki M,

Robine S, Itoh K, Yoshioka K, Kakizaki F, Kitamura T, Oshima M, Taketo MM. Suppression of Colon Cancer Metastasis by Aes through Inhibition of Notch Signaling. Cancer Cell 19:125-137, 2011.

2. Aoki K, Kakizaki F, Sakashita H, Manabe T, Aoki M, Taketo MM. Suppression of Colonic Polyposis by Homeoprotein CDX2 through its Nontranscriptional Function that Stabilizes p27Kip1. Cancer Res. 71:593-602, 2011.

3. Kakizaki F, Aoki K, Miyoshi H, Carrasco N, Aoki M, Taketo, MM. CDX transcription factors positively regulate expression of solute carrier family 5, member 8 in the colonic epithelium. Gastroenterology 138:627-635, 2010.

4. Arimura S, Matsunaga A, Kitamura T, Aoki K, Aoki M, Taketo MM. Reduced level of Smoothened suppresses intestinal tumorigenesis by down-regulation of Wnt signaling. Gastroenterology 137:629-638, 2009.

5. Fujishita T, Aoki K, Lane HA, Aoki M, Taketo MM. Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice. Proc. Natl.Acad. Sci. U S A. 105:13544-13549, 2008.

❶ Suppression of Colon Cancer Metastasis by Aes through Inhibition of Notch Signaling

❷ Stimulation of colon cancer invasion and metastasis by immature myeloid cells (iMCs)

PharmacologyProfessor : Makoto Mark Taketo Senior Lecturer : Masahiro Sonoshita Assistant Professor : Koji Aoki TEL : +81-75-753-4477 FAX : +81-75-753-4402 e-mail : [email protected] URL : http://www4.mfour.med.kyoto-u.ac.jp/

Pharmacology

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- Basic Medicine (Core Departments) - Bioregulation

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Since 1907 the department had focused on human pathology until 1998. In 1998, the standing point largely changed from human pathology to molecular biology of diseases based on modern gene technology and cellular biology in mice and drosophila.

Research and EducationWe Are Challenging Basic And Clinical Studies Focusing On ASPDs In AD. To achieve a vibrant aging society, we must understand the basic mechansim and a fundermental cure for Alzheimer's disease (AD). Amyloid β-protein (Aβ) assemblies are thought to play primary roles in AD. Threre were many challenges to establish antibody therapies, based on the antibodies that targets multiple types of Aβ assemblies. But clinical studies have demonstrated side effects of those antibodies.Recently, we identified ASPD, a possible cause of neuronal cell death in AD patient, for the first time. We also obtained the ASPD toxicity-neutralizing antibodies(Noguchi et al, JBC2009).Now we are trying to develop a therapeutic application of ASPD antibodies and to understand the molecular basis of ASPD formation, neuronal cell death in AD.

Recent Publications1. Yoshida S., Sukeno M., Nabeshima Y. A Vascular-associated niche for undifferentiated

spermatogonia in the mouse testis. Science 317, 1722-1726 (2007) 2. Imura A., Tsuji Y., Murata M., Maeda R. Kubota K., Iwano A., Obuse C., Togashi K., Tominaga

M., Kita N., Tomiyama K., Iijima J., Nabehsima Y., Fujioka M., Asato R., Tanaka S., Kojima K., Ito J., Nozaki K., Hashimoto N., Ito T., Nishio T., Uchiyama T., Fujimori T., Nabehsima Y. alfa-Klotho as a regulator of Calcium homeostasis. Science 316, 1615-1618 (2007)

3. Kurotaki Y. Hatta K., Nakao K., Nabeshima Y., Fujimori T. Blastocyst axis is specified independently of early cell lineage but aligns with the ZP shape. Science 316, 719-723 (2007)

4. Nakagawa T., Nabeshima Y., Yoshida S. Functional identification of the actual and potential stem cell compartments in mouse spermatogenesis. Dev. Cell 12, 1-12 (2007)

5. Kawauchi T., Chhama K., Nabeshima Y., Hoshino M., Cdk5 phosphorylates and stabilizes p27kip1, contributing to cortical neuronal migration. Nature Cell Biol. 8(1) 17-26 (2006)

6. Dezawa M., Ishikawa H., Itokazu Y., Yoshihara T., Hoshino M., Takeda S., Ide C., Nabeshima Y. Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 309, 314-317 (2005)

7. Hoshino M., Nakamura S. Mori K., Kawauchi T., Terao M., Nishimura Y.V., Fukuda A., Matsuo N., Sone M., Terashima T., Wright C. V.E., Kawauchi Y., Nakao K., Nabeshima Y. ptf1a, a bHLH transcription gene, defines GABAergic neuronal fates in cerebellum. Neuron 47, 201-213 (2005)

The Takeda Prize for Medical Science 2007The Uehara Prize 2005

❶ Immunoisolation of ASPD

❷ The amount of ASPDs correlates with the desease progression

Pathology and Tumor BiologyAssociate Professor : Minako Hoshi Assistant Professor : Shinji Itoh TEL : +81-75-753-4426 FAX : +81-75-753-4676 URL : http://lmls.med.kyoto-u.ac.jp

Pathology and Tumor Biology

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- Basic Medicine (Core Departments) - Pathology and Tumor Biology


Pathology is the school of science that takes advantage of any methodology for the understanding of the diseases. Our laboratory has been achieving many feats in the experimental oncology such as the discovery of Fujinami Sarcoma Virus, which was named after the founder of our department, Professor Akira Fujinami. We succeed this tradition and attempt to decipher the enigma of cancer development by using variety of techniques, which includes Fluorescence resonance energy transfer (FRET) imaging, two-photon excitation fluorescence microscopy, and computer simulation.

Michiyuki Matsuda, M.D., Ph.D.Professor

Research and EducationThe basic concept of this department is the cancer research based on the morphological methods. We have been developing FRET probes for the monitoring of oncogene products in living cells. The first successful image of Ras activation reported in 2001 can be found in many textbooks of cell biology. To date this research group has been developed more than 20 probes for G proteins, kinases, and phospholipids. These probes are used to visualize the growth signal transduction cascades and to collect parameters that determine the property of this signaling system. Such parameters are invaluable in that they provide the foundation of the virtual cancer cells. Students in our department come from schools of medicine, biology, physics, and so on. They are enthusiastically learning not only modern molecular biology and pathology, but also bioimaging and system biology. We pay particular focus on the teaching of English communication. Many students present their data in the meetings abroad.

Recent Publications1. Yoshiki,S., Matsunaga-Udagawa,R., Aoki,K., Kamioka,Y., Kiyokawa,E., and Matsuda,M. Ras and

calcium signaling pathwaysconverge at Raf1 via the Shoc2 scaffold protein. Mol. Biol. Cell. 21(6) : 1088-96, 2010.

2. Elfenbein A, Rhodes JM, Meller J, Schwartz MA, Matsuda M, and Simons M. Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKC alpha in a Rac1 activation pathway. J.Cell Biol. 186:75-83, 2009.

3. Kitano M, Nakaya M, Nakamura T, Nagata S, and Matsuda M. Imaging of Rab5 activity identifies essential regulators for phagosome maturation. Nature 453:241-245, 2008.

4. Aoki K, Nakamura T, Inoue T, Meyer T, and Matsuda M. An essential role for the SHIP2-dependent negative feedback loop in neuritogenesis of NGF-stimulated PC12 cells. J.Cell Biol. 177:817-827, 2007.

5. Kawase K, Nakamura T, Takaya A, Aoki K, Namikawa K, Kiyama H, Inagaki S, Takemoto H, Saltiel AR, and Matsuda M. GTP hydrolysis by the Rho family GTPase TC10 promotes exocytic vesicle fusion. Dev. Cell 11: 411-421, 2006.

❶ Activity change of Rac1 GTPase during cytokinesis of Hela cells

❷ Kinetic simulation model of Ras/Raf/MEK/ERK cascade

❸ S imu la t i on mode l o f EGF receptor signaling

❹ Video image of gl ioma cell invasion into the brain

Pathology and Biology of DiseasesProfessor : Michiyuki Matsuda Senior Lecturer : Etsuko Kiyokawa TEL : +81-75-753-4697(office),

9450 (laboratory) FAX : +81-75-753-4655 (office),

4698 (laboratory) e-mail : [email protected] [email protected] URL : http://www.lif.kyoto-u.ac.jp:80/labs/

fret/

Pathology and Biology of Diseases

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- Basic Medicine (Core Departments) - Basic Pathology


The Department of Diagnostic Pathology was established in 1980, and has long been recognized as a branch laboratory of investigative pathology and clinical pathology. Diagnostic pathology is a clinical application of proteomics and cellular pathology, contributing to determination of treatment strategy and evaluation of effects of treatment. In accordance with reorganization of the departments of investigative pathology, our department is now responsible for all autopsies and education of systemic pathology for undergraduate students as well as examination and interpretation of surgical specimens and cytopathological specimens in Kyoto University.

Hironori HagaProfessor

Research and EducationMembers of the department are experts in surgical pathology of several organs and some specific diseases. They pursue individual research projects in close cooperation with clinicians and other biomedical researchers. Most of our researches are clinically oriented, and our goal is to provide accurate and scientific diagnosis based on histology and cytology.Current clinical researches include 1) analysis of allograft rejection and other complications after organ transplantation, 2) diagnosis of rare cervical cancers, 3) study on IgG4-related systemic diseases. Other current and previous study included analysis of duodenal cancer, lung cancer, bone tumors, and so on. More basic themes are 1) elucidation of JAK2/STAT5 pathway in development of hematologic malignancies, 2) chimerism and senescence of the liver allograft, and 3) treatment of mast cell disorders. In addition to these studies initiated by pathology members, we are involved in several projects lead by clinicians. Education for graduate students is combination of research and advanced training for diagnostic pathology. Subspecialty training for surgical pathology or cytopathology is encouraged in combination with basic investigative research and /o r t r ad i t i ona l pa tho logy s tudy us ing immunohistochemistry and in situ hybridization. Complete in-house digital pathology database and image analysis using virtual microcopy are also available.

Recent Publications1. Tsuruyama T, Nakai T, Hiratsuka T, Jin G, Nakamura T, Yoshikawa K. In vitro HIV-1 selective

integration into the target sequence and decoy-effect of the modified sequence. PLoS One. 2010;5:e13841.

2. Miyagawa-Hayashino A, Egawa H, Yorifuji T, Hasegawa M, Haga H, Tsuruyama T, Wen MC, Sumazaki R, Manabe T, Uemoto S. Allograft steatohepatitis in progressive familial intrahepatic cholestasis type 1 after living donor liver transplantation. Liver Transpl. 2009;15:610-8.

3. Mikami Y, Kiyokawa T, Sasajima Y, Teramoto N, Wakasa T, Wakasa K, Hata S. Reappraisal of synchronous and multifocal mucinous lesions of the female genital tract: a close association with gastric metaplasia. Histopathology. 2009;54:184-91.

4. Fujimoto M, Haga H, Okamoto M, Obara E, Ishihara M, Mizuta N, Nishimura K, Manabe T. EBV-associated diffuse large B-cell lymphoma arising in the chest wall with surgical mesh implant. Pathol Int. 2008;58:668-71.

5. Yamashita K, Haga H, Kobashi Y, Miyagawa-Hayashino A, Yoshizawa A, Manabe T. Lung involvement in IgG4-related lymphoplasmacytic vasculitis and interstitial fibrosis: report of 3 cases and review of the literature. Am J Surg Pathol. 2008;32:1620-6.

❶ Endothel ial chimer ism. Original donor endothelium ( g r e e n ) m i x e d w i t h r e c i p i e n t - d e r i v e d endothelial cells (brown) reflecting portal fibrosis and neovessel formation.

❷ C 4 d - p o s i t i ve c h r o n i c r e j e c t i o n a f t e r l i v e r transplantation.

❸ IgG4-related lung disease showing vasculit is with IgG4-positive plasma cells.

❹ Staffs.

Diagnostic PathologyProfessor : Hironori Haga Associate Professor : Yoshiki Mikami, Sachiko Minamiguchi Senior Lecturer : Aya Miyagawa-Hayashino Assistant Professor : Shinji Sumiyoshi TEL : +81-75-751-3488 FAX : +81-75-751-3499 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Diagnostic Pathology

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- Basic Medicine (Core Departments) - Basic Pathology


The clinical outcome of infection is the result of a battle between bacterial virulence factors and the host defense system. It is becoming increasingly important to understand the basic mechanism of bacteria-host interaction under the current situation where bacteria acquire antibiotic resistance. We have been particularly interested in the intracellular parasitic bacteria that are capable of escaping the macrophage killing. Our aim is to elucidate the molecular mechanism of survival of Listeria and Mycobacteria, representative intracellular parasitic bacteria, and the host immune response to these microbes.

Masao Mitsuyama, M.D., Ph.D.Professor

Research and Education1. Virulence factor of Listeria and the host responseThe ability of Listeria monocytogenes to evade the intracellular killing by macrophages depends mainly on its virulence locus called LIPI-1. By constructing the deficient mutant for the genes locating in this locus, we have found that LLO encoded by hly plays a critical role in the induction of host cytokine response in addition to its role for cytosolic invasion. The precise relationship between the LLO structure and the cytokine-inducing ability has been analyzed and reported. Our current research is trying to clarify the molecular mechanism in inflammasome formation and induction of type I interferon in infected macrophages by using construction of various mutant or recombinant strains, mice deficient for candidate genes or SiRNA.2. Virulence factor of Mycobacteria and the host responseOne of the major candidates for the virulence of M. tuberculosis is RD1 locus that encodes various protein probably comprising a type VII secretion system. By using RD1 deficient mutant and complemented strains, we have found that RD1 is involved in the host cell necrosis and induction of IL-1α,β processing. We are now trying to find out how the effector proteins encoded by RD1 locus induce such response of host macrophages. Another candidate is PPE proteins in one of which we have found the inhibitory activity for host cytokine response. Our recent studies have revealed that PD1/PDL-1 pathway of the host plays a pivotal role in the pathophysiology of infected mice. Thus, mycobacterial virulence factors and host response are under investigation from a various point of view. As our laboratory has a number of students from abroad, we use English at our journal club or data discussion.

Recent Publications1. Hara H, Tsuchiya K, Nomura T, Kawamura I, Shoma S & Mitsuyama M : Dependency of

caspase-1 activation induced in macrophages by Listeria monocytogenes on cytolysin, Listeriolysin O, after evasion from phagosome into the cytoplasm. J. Immunol. 180: 7859-7868, 2008.

2. Kurenuma T, Kawamura I, Hara H, Uchiyama R, Daim S, Dewamitta SR, Sakai S, Tsuchiya K, Nomura T & Mitsuyama M. : RD1 locus in Mycobacterium tuberculosis genome contributes to activation of caspase-1 via induction of potassium ion efflux in infected macrophages. Infect. Immun. 77: 3992-4001, 2009.

3. Tsuchiya K, Hara H, Kawamura I, Nomura T, Yamamoto T, Daim S, Dewamitta SR, Shen Y, Fang R, & Mitsuyama M. : Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. J. Immunol. 185: 1186-1195, 2010.

4. Dewamitta SR, Nomura T, Kawamura I, Hara H, Tsuchiya K, Kurenuma T, Shen Y, Daim S, Yamamoto T, Qu H, Sakai S, Xu Y & Mitsuyama M. : Listeriolysin O-dependent bacterial entry into the cytoplasm is required for calpain activation and interleukin-1 alpha secretion in macrophages infected with Listeria monocytogenes. Infect. Immun. 78 : 1884-1894,2010.

5. Sakai S, Kawamura I, Okazaki T, Tsuchiya K, Uchiyama R & Mitsuyama M.: PD-1-PD-L1 pathway impairs Th1 immune response in the late stage of infection with Mycobacterium bovis bacillus Calmette-Guérin. Int. Immunol. 22: 915-925, 2010.

❶ Construction of recombinant L. monocytogenes strains differing in hly gene, the g r ow t h o f e a c h s t ra i n i n s i d e m a c r o p h a g e s ( i m m u n o f l u o r e s c e n c e m i c r o s c o p y ) a n d t h e ability to induce caspase-1 activation (western blotting).

❷ 2 R D 1 r e g i o n o f M . t u b e r c u l o s i s p l ay s a n e s s e n t i a l r o l e i n t h e i n d u c t i o n o f h o s t c e l l necrosis, processing and secretion of IL-1a and IL-1b in infected macrophages.

❸ Lab Staffs (as of February, 2011)

MicrobiologyProfessor : Masao Mitsuyama Associate Professor : Ikuo Kawamura Assistant Professor : Kohsuke Tsuchiya, Hideki Hara TEL : +81-75-753-4441, 4448 FAX : +81-75-753-4446 e-mail : [email protected] URL : http://bisei15.mb.med.kyoto-u.ac.jp/

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Microbiology

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- Basic Medicine (Core Departments) - Infectious Diseases and Immunology


Immunology constitutes an essential part in almost every field of modern medicine, and understanding of immune mechanisms has greatly contributed to the medical progress in many aspects. Despite the amazing advances in immunology for recent decades, however, major immunological issues remain to be unveiled, and immunology continues to be one of the most mysterious and challenging fields in modern biology and medicine. Research efforts in our laboratory are focused on understanding the central issues in immunology, including the development of immune system, mechanisms of tumor immunity, autoimmunity and leukemia development.

Nagahiro Minato, M.D., Ph.D.Professor

Research and EducationCurrent major research activities in the laboratory are focused on two aspects; first, understanding of the mechanisms and regulation of normal immune system and elucidating how dysregulation of normal development leads to life-threatening diseases such as autoimmune diseases, immunodeficiency and leukemia; second, understanding of the mechanisms of possible immune surveillance against autonomously arising malignant cells and applying the principles for effectively controlling human cancer. We are studying these crucial issues with the use of feasible animal models including gene-engineered animals in close conditions to “reality” as much as possible. Our key word is “ nature, but not we, decides the way to go”. This laboratory is primarily responsible for the education of Immunology for both undergraduate and graduate students of Kyoto University School of Medicine. There are many graduate students at Master and PhD courses of both Graduate School of Medicine and Graduate School of Biostudies, including foreign students, and they are included in several specific research projects under the instruction of 4 faculty staff members with regular English-based laboratory meetings.

Recent Publications1. Kawai. K. Hamazaki, Y., Fujita, H., Fujita, A., Sato, T., Moriwaki, K., Furuse, M. , Fujimoto,

T., Agata, Y. and Minato, N. (2011) Claudin-4 is induced in thymocytes of late CD4/CD8 double positive stage by E2A and promotes alpha BetaT cell receptor–mediated positive selection. Proc. Nat. Acad. Sci. USA. in the press.

2. Shimatani, K., Nakashima, Y., Hattori, M., Hamazaki, Y., and Minato, N. (2009) Memory phenotype PD-1+ CD4+ T cells expressing C/EBP alpha underlie T cell immunodepression in senescence and leukemia. Proc. Nat. Acad. Sci. USA. 106;15807-15812.

3. Hamazaki, Y, Fujita, H, Kobayashi, T, Choi, Y, H. Scott, Matsumoto, M, and Minato, N. (2007) Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from claudin-expressing cells. Nature Immunol. 8:304-311.

4. Minato, N, K. Kometani, and M.Hattori. (2007) Regulation of immune responses and hematopoiesis by the Rap1 signal. (Review) Adv. Immunol. 93: 229-264.

5. Ishida, D., Su, L., Shinozuka, Y., Tamura,A., Katayama, Y., Kawai, Y., Wang, S-F, Taniwaki, M., Hamazaki, Y., Hattori, M., and Minato, N. (2006) Rap1 Signal Controls B Cell Receptor Repertoire and Generation of Self-reactive B1 Cells. Immunity, 24,417-427.

❶ Myeloproliferative disorders by deregulated Rap signaling (from cover page of Cancer Cell)

❷ Development thymic epithelial cells (from Nature Immunol.)❸ Laboratory members

Immunology and Cell BiologyProfessor : Nagahiro Minato Associate Professor : Yasutoshi Agata, Yoko Hamazaki Assistant Professor : Yasuhiro Nakashima Program-Specific Associate Professor : Yoshimasa Tanaka TEL : +81-75-753-4659 FAX : +81-75-753-4403 e-mail : [email protected] URL : http://www.imm.med.kyoto-u.ac.jp/

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Immunology and Cell Biology

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- Basic Medicine (Core Departments) - Infectious Diseases and Immunology


The Department of Forensic Medicine and Molecular Pathology at Kyoto University has a proud legacy which can be traced back to 1899 when the Department was first founded. Since its establishment, the Department has been an active force in promoting the significance and importance of forensic medicine through innovative programs, educational initiatives, research and analysis and advocacy for better forensic practices, policies and laws.

Keiji Tamaki, M.D.,Professor

Research and EducationOur department is engaged in a number of ongoing research projects which encompasses a wide range of topics with DNA polymorphisms and genomic DNA rearrangement at its core. While numerous in amount, our efforts are currently concentrated on three major themes: screening/analyzing mutations which occur during chromosomal crossover events in germline cells; dissecting the depth and breadth of microsatellite instability in the B-cell lymphoblastic lymphoma genome; and elucidating the role of retrovirus and transposon integration in promoting somatic cell mutations. Minisatellite AnalysisThe discovery and evolution of microsatellite-based analytical techniques has all but marginalized minisatellite research, however one of the defining characteristics of the human genome—which distinguishes it from other primates—is the highly polymorphic nature of minisatellites. Minisatellites are commonly observed in and around telomeric regions in eukaryotic genomes, and consist of arrays of widely dispersed 6-to 100-bp repeats. While other highly polymorphic regions (microsatellites or STRs) are exploited for use in such avenues as individual identification and paternity testing in the realm of forensics, the groundwork for our forensic and population genetic research endeavors is based on minisatellites.Retroviruses and Pathological ResearchTo augment our existing arsenal, we have expanded our activities to address the issues at the core of modern microbiological research. In collaboration with a number of globally renowned departments of basic medicine, we have expanded our efforts to include identifying the retroviral mechanisms underlying lymphomagenesis; erecting the framework for individual identification techniques utilizing in situ hybridization with probes; development of novel strategies in differential diagnosis based on enhanced immunohistochemical methods along with its application to identifying chimerisms in acute and chronic allograft rejection; molecular evaluation on the activation of antigen presenting cells (APCs); and exploiting immunocompetent cell response as a prognostic factor in colorectal cancer (CRC).Autopsy Imaging (AI) and TrainingIn addition to research in basic medicine, we are one of the pioneering institutes to initiate research in the revolutionary field of Autopsy Imaging. In the near future, we hope to include routine diagnostic imaging to our forensic autopsies in order to identify the natural and/or external factors which contributed to the death of an individual.Autopsies remain a critical component of the services we provide to the community. In order to meet the demands for future forensic pathologists, we’ve erected an integrated training initiative in collaboration with the Department of Diagnostic Pathology, Kyoto University Hospital. Under this program, post-graduate students receive intensive training in Surgical Pathology to supplement their research and clinical commitments.

Recent Publications1. Tsuruyama T, Hiratsuka T, Jin G, Imai Y, Takeuchi H, Maruyama Y, Kanaya K, Ozeki M,

Takakuwa T, Haga H, Tamaki K, Nakamura T. MLV integration indeces the formation of transcription factor complexes on palindromic sequences in the Stat5a gene during the development of pre-B lymphomagenesis. Am J Pathol. 2010 (in press)

2. Yoshida K, Yayama K, Hatanaka A, Tamaki K. Efficacy of extended kinship analyses utilizing commercial STR kit in establishing personal identification. Legal Med 2011;13:12-5

3. Tsuruyama T, Nakai T, Hiratsuka T, Jin G, Nakamura T, Yoshikawa K. In vitro HIV-1 integration into the target sequence and decoy-effect of the modified sequence. PLsS One 2010;5(11):e13841.

4. Tsuruyama T, Imai Y, Takeuchi H, Hiratsuka T, Maruyama Y, Kanaya K, Kaszynski R, Jin G, Okuno T, Ozeki M, Nakamura T, Takakuwa T, Manabe T, Tamaki K, Hiai H. Dual retrovirus integration tagging: identification of new signaling molecules Fiz1 and Hipk2 that are involved in the IL-7 signaling pathway in B lymphoblastic lymphomas. J Leukoc Biol. 2010;88(1):107-16.

5. Kaszynski RH, Akatsuka S, Hiratsuka T, Jin G, Ozeki M, Okuno T, Nakamura T, Manabe T, Takakuwa T, Hiai H, Toyokuni S, Tamaki K, Tsuruyama T. A quantitative trait locus responsible for inducing B-cell lymphoblastic lymphoma is a hotspot for microsatellite instability. Cancer Sci. 2010;101(3):800-5.

6. Shibasaki S, Imagawa A, Tauriainen S, Iino M, Oikarinen M, Abiru H, Tamaki K, Seino H, Nishi K, Takase I, Okada Y, Uno S, Murase-Mishiba Y, Terasaki J, Makino H, Shimomura I, Hyöty H, Hanafusa T. Expression of toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes. Endocr J. 2010;57(3):211-9.

❶ Example of minisatellite allele mapping via MVR-PCR❷ Distribution of the likelihood ratio in sibship assessment utilizing varying numbers of

alleged siblings ❸ Model of STAT5A signal transduction pathway in B-cell lymphoblastic lymphoma ❹ Autopsy room equipped with the latest digital equipment ❺ Photo of Department members taken during cherry blossom season

Forensic Medicine and Molecular PathologyProfessor : Keiji Tamaki Associate Professor : Tatsuaki Tsuruyama Assistant Professor : Munetaka Ozeki, Hirokazu Kotani TEL : +81-75-753-4474 FAX : +81-75-761-9591 e-mail : [email protected] URL : http://square.umin.ac.jp/kyo_houi/

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Forensic Medicine and Molecular Pathology

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- Basic Medicine (Core Departments) - Legal Medicine


❶ MFG-E8-/- mice(-/-) show the enlarged and activated germinal centers (PNA-positive area), produce auto-antibodies, and develop S L E - t y p e a u t o i m mu n e disease.

❷ DNase II-/- mice develop chronic polyarthritis.

❸ The structure of TMEM16F that catalyzes scrambling of phospholipids on the plasma membranes

❹ Members of the Department.

Science is a fun. We hope that members in our Department have a full of curiosity to science, work hard, and enjoy Science. Using various techniques of Biochemistry and Molecular Biology, we are trying to unveil the mystery in life. Our devotion to science would contribute to the understanding of human diseases. Following the tradition of our Department that had been created by Former Professors Torasaburo Araki, Osamu Hayaishi, Tasuku Honjo, and others, we wish to create a new wave in Medical Chemistry.

Shigekazu Nagata, Ph.D.Professor

Research and EducationIn our laboratory, we are studying the molecular mechanism of cell death, and its physiological and pathological roles. We identify molecules that are involved in cell death, and characterize them using techniques of Biochemistry, Molecular Biology, and mouse Genetics. We identified Fas ligand, a cytokine, that induces apoptosis in cells, and showed that apoptosis is executed by caspases (proteases) and CAD (caspase-activated DNase). Inefficient apoptosis by lack of the Fas ligand or its receptor Fas causes lymphoproliferation, leading to autoimmune diseases. Whereas, the excessive apoptosis by Fas ligand causes tissue destruction such as hepatitis. Apoptotic dead cells are swiftly engulfed by macrophages and degraded in lysosomes. We identified proteins (MFG-E8 and Tim-4) that is involved in engulfment of apoptotic cells, and showed that if apoptotic cells are not efficiently engulfed, they undergo secondary necrosis, leading to SLE (systemic lupus erythematosus)-type autoimmune diseases. We also identified an enzyme (DNase II) that digests chromosomal DNA of apoptotic cells after macrophage engulf them. If macrophages cannot digest DNA, they are activated and produce various cytokines including IFNb(beta) and TNFa(alpha), causing severe anemia or chronic polyarthritis. Phospholipids on plasma membranes are asymmetrically distributed between inner and outer leaflets. When cells undergo apoptosis, or platelets are activated, this asymmetrical distribution is disrupted, and phosphatidylserine exposed on the cell surface functions as an “eat me” signal, or trigger the blood clotting. We recently identified an enzyme (scramblase) that causes the exposure of phosphatidylserine on the activated platelets.

Recent Publications1. Yoshida, H., Kawane, K., Koike, M., Mori, Y., Uchiyama, Y. and Nagata, S.: Phosphatidylserine-

dependent engulfment by macrophages of nuclei from erythroid precursor cells. Nature 437: 754-758, 2005.

2. Kawane, K., Ohtani, M., Miwa, K., Kizawa, T., Kanbara, Y., Yoshioka, Y., Yoshikawa, Y. and Nagata, S.: Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443: 998-1002, 2006.

3. Miyanishi, M., Tada, K., Koike, M., Uchiyama, Y., Kitamura, T. and Nagata, S.: Identification of Tim-4 as a phosphatidylserine receptor. Nature 450: 435-439, 2007.

4. Okabe, Y., Sano, T. and Nagata, S.: Regulation of the innate immune response by threonine phosphatase of Eyes absent. Nature 460: 520-524, 2009.

5. Suzuki, J., Umeda, M., Sims, P. J., and Nagata, S.: Calcium-dependent phospholipid scrambling by TMEM16F. Nature 468: 834-838, 2010.

Medical ChemistryProfessor : Shigekazu Nagata Assistant Professor : Rikinari Hanayama, Jun Suzuki TEL : +81-75-753-9441, +81-75-753-9445 FAX : +81-75-753-9446 e-mail : [email protected] URL : http://www2.mfour.med.kyoto-u.

ac.jp/~nagata/

Medical Chemistry

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- Basic Medicine (Core Departments) - Molecular Medicine


Membrane proteins govern the basic cellular processes of signal transduction,the generation of electrical signals, molecular transport and energy conservation. In spite of the abundance and importance of membrane proteins there are only ca 120 unique membrane protein structures have been determined. Our laboratory is studying the structures of various membrane proteins and developing the methodologies in membrane protein crystallography in cooperation with ERATO Iwata Human Receptor Crystallography Project(http://cell.mfour.med.kyoto-u.ac.jp), the MPL group at British synchrotron radiation facility, Diamond, and the MPC group(http://www3.imperial.ac.uk/lifesciences/research/molecularbiosciences/membraneproteincrystallography) at Imperial College London. Our laboratory is ideal for the students aspired to build up an international career.

So Iwata,Ph.DProfessor

Research and EducationThe results of various genome projects have shown that up to 30% of human proteins occur in cell membranes. Membrane proteins play crucial roles in many biological functions and are of key importance for medicine. Over 50% of commercially available drugs target membrane proteins.

We are currently focusing to determine medically relevant membrane protein structures. These are the G protein-coupled receptors (GPCR), transporters (especially those for drugs, peptides, and sugars) and enzymes involved in steroid synthesis or metabolism. These membrane protein structures will provide a basic understanding of life at the molecular level and could boost computer aided rational design of new drugs, which could reduce the number of animal experiments and unwanted side effects.

Graduate students in our laboratory are expected to learn a series of techniques of protein crystallography from expression to X-ray crystallographic analysis and to solve a protein structure. The targets will be those listed above or related proteins. These projects are challenging but designed to be completed within a few years.

Recent Publications1. Horsefield, R, Yankovskaya, V, Sexton, G, Whittingham, W, Shiomi, K, Omura, S, Byrne, B,

Cecchini, G, Iwata, S. (2006) Structural and computational analysis of the quinone-binding site of complex II (succinate-ubiquinone oxidoreductase): a mechanism of electron transfer and proton conduction during ubiquinone reduction. (2006) J. Biol. Chem. 281(11) 7309 – 7316

2. Mirza, O, Guan, L, Verner, G, Iwata, S, Kaback, HR. Structural evidence for induced fit and a mechanism for sugar/H+ symport in LacY. (2006) EMBO J. 25(6) 1177 - 1183

3. Makyio, H, Iino, R, Ikeda, C, Imamura, H, Tamakoshi, M, Iwata, M, Stock, D, Bernal, RA, Carpenter, EP, Yoshida, M, Yokoyama, K, Iwata, S. (2005) Structure of a central stalk subunit F of prokaryotic V-type ATPase/synthase from Thermus thermophilus, EMBO J. 24(22) 3974 – 3983

4. Ferreira, KN, Iverson, TM, Maghlaoui, K, Barber, J, Iwata, S. Architecture of the photosynthetic oxygen-evolving center (2004) Science 303(5665) 1831 - 1838

5. Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S. (2003) Structure and mechanism of the lactose permease of Escherichia coli Science 301(5633) 610-615

❶ C r ys ta l s t r uc tu re o f l ac tose permiase from Escherichia coli. A homologue of glucose transporters implicated in diabetes

❷ Crystal structure of Photosystem II from Thermosynechococcus elongates. Split water molecules using solar energy to evolve m o l e c u l a r o x y g e n i n t h e atmosphere.

Cell BiologyProfessor : So Iwata Senior Lecturer : Takuya Kobayashi Assistant Professor : Makoto Adachi, Norimichi Nomura TEL : +81-75-753-4372 FAX : +81-75-753-4660 e-mail : [email protected] URL : http://cell.mfour.med.kyoto-u.ac.jp/

Cell Biology

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- Basic Medicine (Core Departments) - Molecular Medicine


Cancer originates from a small number of normal cells (often a single cell) in the body that progressively acquire un-controllable, proliferative potentials and eventually form tumors. Cancer is sometimes called “disease of the cell” or “disease of genes”, since cancer-derived cells have some properties distinguishable from those of normal counterparts and since these special properties can be attributed to genetic alterations or mutations. Molecular Oncology is the research field where scientists try to discover molecules (and their alterations) underlying the malignant behaviors of cancer cells, to elucidate their functions, and to utilize the knowledge and materials obtained from such studies in developing effective methods of cancer therapy. The main focus of our research group is to find and characterize molecules that play important roles in the malignant behaviors of cancer cells such as recruitment of capillary blood vessels (or angiogenesis), invasion, and metastasis. Makoto Noda, Ph.D.

Professor

Research and EducationIt has been know for more than 30 years that cell hybrids between normal cells and cancer cells show non-malignant phenotype. It was also found that the DNA extracted from cancer cells can confer malignant phenotype when introduced into normal cells. These apparently conflicting findings are considered today to indicate the presence of multiple types of mutations in cancer cells: i.e., inactivation of tumor suppressor genes and activation of cancer-causing genes (or oncogenes). Through screening the genes with ability of normalizing the malignant phenotype of cancer cells, we have discovered RAP1A and RECK. RECK is decreased in many kinds of solid tumors, and when artificially expressed, it inhibits the ability of cancer cells to invade, metastasize, and recruit blood vessels (angiogenesis). Hence, our study of RECK may help developing new diagnostic and therapeutic methods. We have also shown that RAS oncogenes may be involved in differentiation and even tumor suppression depending on cell type. Through screening of genes up-regulated in early stages of brain development, we have discovered several novel molecules with interesting bio-activities such as Nedd2/caspase-2 (a protease executing apoptosis), Nedd4 (ubiquitin ligase), Nedd5/Sept2 (novel cytoskeletal protein involved in cell division), and Nedd8 (ubiquitin-related protein modifier). In a friendly and inspiring atmosphere, graduate students with various backgrounds (including several foreign fellows) are struggling to solve the important puzzles of how cancer cells behave selfishly and how they can be tamed.

Recent Publications1. Wang H, Imamura Y, Ishibashi R, Chandana EP, Yamamoto M, Noda M. The Reck tumor

suppressor protein alleviates tissue damage and promotes functional recovery after transient cerebral ischemia in mice. J Neurochem 115, 385-398 (2010).

2. Shamma A, Takegami Y, Miki T, Kitajima S, Noda M, Obara T, Okamoto T, Takahashi C. Rb Regulates DNA damage response and cellular senescence through E2F-dependent suppression of N-ras isoprenylation. Cancer Cell 15, 255-269 (2009).

3. Omura A, Matsuzaki T, Mio K, Ogura T, Yamamoto M, Fujita A, Okawa K, Kitayama H, Takahashi C, Sato C, Noda M. RECK forms cowbell-shaped dimers and inhibits matrix metalloproteinase-catalyzed cleavage of fibronectin. J Biol Chem 284, 3461-3469 (2009).

4. Morioka Y, Monypenny J, Matsuzaki T, Shi S, Alexander DB, Kitayama H, Noda M. The membrane-anchored metalloproteinase regulator RECK stabilizes focal adhesions and anterior-posterior polarity in fibroblasts. Oncogene 28, 1454-1464 (2009).

5. Muraguchi T, Takegami Y, Ohtsuka T, Kitajima S, Chandana EP, Omura A, Miki T, Takahashi R, Matsumoto N, Ludwig A, Noda M, Takahashi C. RECK modulates Notch signaling during cortical neurogenesis by regulating ADAM10 activity. Nat Neurosci 10, 838-845 (2007).

❶ Activated RAS oncogenes i n d u c e n e u r o n a l differentiation in PC12 cells (Nature 318: 73-75, 1985).

❷ RAP1A/Krev1 encoding a low molecular weight G-protein was discovered a s a t r a n s f o r m a t i o n suppressor gene against an activated RAS oncogene (Cell 56: 77-84, 1989).

❸ Another transformation suppressor gene RECK encodes a membrane-anchored regu la to r o f matrix metalloproteinases (MMP). RECK is down-regulated in many cancers and suppresses tumor angiogenesis, invasion, and metastasis when expressed in such cancer cells (PNAS 95, 13221-13226, 1998; Cell 107: 789-800, 2001).

❹ Laboratory members

Molecular OncologyProfessor : Makoto Noda Associate Professor : Hitoshi Kitayama Assistant Professor : Tomoko Matsuzaki, Yoko Yoshida TEL : +81-75-751-4150 FAX : +81-75-751-4159 e-mail : [email protected] URL : http://www.users.iimc.kyoto-u.ac.jp/

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Molecular Oncology

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- Basic Medicine (Core Departments) - Molecular Biology


Our long-term goal is to use spermatogonial stem cells for genetic modification. We have recently succeeded in long-term culture of mouse spermatogonial stem cells. Due to their unique morphology, we named them germline stem (GS) cells. GS cells have several advantages over ES cells. First, although ES cells are only available during the embryonic period, GS cells can be derived from postnatal animals. Second, they are not tumorigenic and committed to the germline lineage. Given that ES cells with germline potential have been obtained only from mice, our GS cell technology may resolve current challenges with ES cells and greatly contribute to the development of new transgenic technologies. We are now trying 1) to modify the genome of GS cells and 2) to derive GS cells from other animal species.

Takashi Shinohara, M. D., Ph. D.,Professor

Research and EducationSpermatogonial stem cells are the only stem cells in the body that can transmit genetic information to the offspring. Current methods to create transgenic animals are based on oocytes or eggs. Although germline can be efficiently modified in mice, it is inefficient or impossible in other animal species. Our long-term goal is to use spermatogonial stem cells for genetic modification. In 1994, a technique to transfer spermatogonial stem cells was developed. Testis cells transferred into the seminiferous tubules of infertile animals form colonies of spermatogenesis and produce donor-derived offspring by mating with females. Using this technique, we have developed several new methods to manipulate spermatogonial stem cells. It is now possible to 1) purify stem cells, 2) introduce retrovirus into stem cells for transgenic animal production, and 3) treat male infertility by gene therapy. However, due to the lack of culture technique, genetic modification of stem cells was not efficient. We have recently succeeded in long-term culture of mouse spermatogonial stem cells. Due to their unique morphology, we named them germline stem (GS) cells. GS cells have different morphology from embryonic stem (ES) cells, and can grow exponentially in vitro for more than 2 years. Upon transplantation into infertile animals, GS cells can produce normal fertile offspring, indicating that they are real stem cells. GS cells have several advantages over ES cells. First, although ES cells are only available during the embryonic period, GS cells can be derived from postnatal animals. Second, they are not tumorigenic and committed to the germline lineage. Given that ES cells with germline potential have been obtained only from mice, our GS cell technology may resolve current challenges with ES cells and greatly contribute to the development of new transgenic technologies. We are now trying 1) to modify the genome of GS cells and 2) to derive GS cells from other animal species.

Recent Publications1. Kanatsu-Shinohara, M. et al. (2003) Long-term proliferation in culture and germline transmission

of mouse male germline stem cells. Biol. Reprod. 69, 612-616. 2. Kanatsu-Shinohara, M. et al. (2004) Generation of pluripotent stem cells from neonatal mouse

testis. Cell 119, 1001-1012. 3. Kanatsu-Shinohara, M. et al. (2006) Production of knockout mice by random and targeted

mutagenesis in spermatogonial stem cells. Proc. Natl. Acad. Sci. USA 103, 8018-8023. 4. Kanatsu-Shinohara, M. et al.(2008) Homing of mouse spermatogonial stem cells to germline niche

depends on beta1-integrin. Cell Stem Cell 3, 533-542. 5. Lee, J.et al. (2009) Genetic reconstruction of mouse spermatogonial stem cell self-renewal in vitro

by Ras-cyclin D2 activation. Cell Stem Cell 5, 76-86.

❶ Growth of GS cells in vitro ❷ Growth of mGS cells in vitro ❸ people in the lab

Molecular GeneticsProfessor : Takashi Shinohara Assistant Professor : Mito Kanatsu-Shinohara,

Seiji Takashima, Satoshi Tanaka TEL : +81-75-751-4160 FAX : +81-75-751-4169 e-mail : [email protected]

Molecular Genetics

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- Basic Medicine (Core Departments) - Medical Genetics


The Department of Radiation Genetics was founded for the purpose of basic research and education in the field of Radiation Biology in 1961. Dr. Shunichi Takeda took over a departmental Head in 1998, and has studied molecular mechanism of radiotherapy and chemotherapy of tumors by employing a reverse genetic approach using a chicken B lymphocyte line and Medaka fish as model system. Our unique and efficient system allows students to publish their data in qualified journals while quickly learning essence of genetics and experimental techniques.

Shunichi Takeda, M.D., Ph.D.Professor

Research and EducationForward and Reverse genetics is a method for the functional analysis of various proteins. Forward genetics aims to identify mutants with particular malfunctions, that are subsequently used to identify the gene responsible for the observed phenotype. The approach of reverse genetics starts at the opposite end with a gene, whose function needs to be analyzed. Gene disruption by gene targeting technologies in cells or animals, and phenotype analysis of the resulting mutants is a powerful way to learn about the molecular role of genes. We have developed Reverse genetic research systems using the chicken B lymphocyte line DT40, and recently the Medaka fish. We are using these systems to understand the function of a variety of genes in DNA repair, recombination, replication, cell cycle, and its checkpoint regulation. A defect in these processes often leads to tumor genesis. The understanding of the molecular details of these defects is thus useful for development of tailor-made therapy. Moreover, reverse genetic approaches will be used more and more in clinical applications, with the development of efficient gene disruption techniques by siRNA and viral gene therapies.Among cells of higher eukaryotes, DT40 is an ideal model system for reverse genetic studies, because the frequency of gene targeting is increased by two orders of magnitude when compared to mammalian cells. Another advantage is the very stable phenotype of these cells that make it easy to compare different mutants to wild type cells. Using DT40 cells, Ph.D. students can learn all basic molecular and cellular biology techniques in projects involving gene disruption and phenotype analysis, as shown in Figure 1 as an example. Moreover, our students are publishing their results in high-qualified journals. Hence, most first authors in our labs publications are Ph.D. students.Medaka (Figure 2) as well as Zebra-fish as genetic model systems have several advantages over rodents in medical studies. Using this system one can quickly perform a large number of genetic experiments, such as genetic crosses, creation of transgenic fishes, injection of anti-strand RNA into fertilized eggs to specifically suppress any given genes, and storage of mutant lines by making frozen sperm aliquots. Medaka and zebra-fish are complementary to each other because studies of each species have advantages and disadvantages when compared to each other. Our lab was the first to create gene disrupted Medaka fishes in 2005. This break-through will certainly make our medical school the center of excellence in the medical research of Medaka in the world. Making gene disrupted Medaka lines from scratch in any research field of your interest, you will be able to become a pioneer just like the first settlers in America 200 years ago. Once you found a way in this unique system, you will feel no reason to stick to the rodent experimental system, where there are too many old die-hard experts similar to the aristocrats in 18th century Europe.Reverse genetics in these unique experimental systems is highly educative particularly for beginner students. Avoiding fierce competition as in studies on mice and human materials, you will be able to learn effectively from your colleagues because everybody in our laboratory shares the same experimental methods and materials while studying different genes. You can study both systems and publish data in three years to defend your thesis. Seminars are done in English twice a week. We will also support a few months externship in top laboratories in Europe or America during the Ph.D. course.

Recent Publications1. Iijima J, Zeng Z, Takeda S, Taniguchi Y. (2010) RAP80 acts independently of BRCA1 in repair of

topoisomerase II poison-induced DNA damage. Cancer Res. (in press) 2. Hirota K, Sonoda E, Kawamoto T, Motegi A, Masutani C, Hanaoka F, Szuts D, Iwai S, Sale JE,

Lehmann A, Takeda S. (2010) Simultaneous disruption of two DNA polymerases, Pol η(eta)and Pol ζ(zeta), in avian DT40 cells unmasks the role of Pol η(eta) in cellular response to various DNA lesions. PLoS Genet. (in press)

3. Kohzaki M, Nishihara K, Hirota K, Sonoda E, Yoshimura M, Ekino S, Butler JE, Watanabe M, Halazonetis T, Takeda S. (2010) DNA polymerases ν(nu) and θ(theta) are required for efficient Immunoglobulin V gene diversification in chicken. J Cell Biol. 189: 1117-1127.

4. Nakamura K (graduate school student), Kogame T, Takeda S, Taniguchi Y, et al. (9), (2009) Collaborative action of Brca1 and CtIP in elimination of covalent modifications from double-strand breaks to facilitate subsequent break repair. PLoS Genet. (in press)

5. Zhao GY (graduate school student), Takeda S, et al. (10), (2007) A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination. Mol Cell. 25: 663-675.

6. (Review) Kinoshita M, Takeda S. (2007) Connecting the Dots between Septins and the DNA Damage Checkpoint. Cell 130: 777-9.

❶ Ph.D. students can learn all techniques necessary for performing the following experiment within three years. To visualize dynamics of chromosomes during mitosis, Green fluorescent protein (GFP) gene was knocked-in towards the endogenous locus of a kinetochore protein gene, CENP-H in the chicken B lymphocyte line DT40. This GFP tagged CENP-H substituted for loss of wild-type CENP-H protein, indicating that the chimeric protein works normally. Using this newly developed phenotypic assay, we evaluated the role of Scc1 protein by conditional inactivating Scc1, whose homolog is known to be essential for mitotic cell division in yeast. From this result, we conclude that Scc1 promotes association of the spindle body with mitotic chromosomes thereby contributing to accurate transmission of chromosomes to daughter cells.

Radiation GeneticsProfessor : Shunichi Takeda Associate Professor : Kouji Hirota Assistant Professor : Akira Motegi TEL : +81-75-753-4410 FAX : +81-75-753-4419 e-mail : [email protected] URL : http://rg4.rg.med.kyoto-u.ac.jp/

Radiation Genetics

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- Basic Medicine (Core Departments) - Medical Genetics


The primary focus of our research has been on the neuronal circuitry and synaptic organization of the mammalian brain, and the ultimate goal is to elucidate the neuronal design and mechanism that produces the ‘mind’. To this end, various pathways in the brain and spinal cord are analysed morphologically with light and electron microscopes by means of tracer techniques, immunocytochemistry, in situ hybridization histochemistry, and intracellular recording/staining method. Recently, the efforts are strongly focused on (1) the development and application of the molecular-biological tools for completely visualizing the neuronal processes, such as the viral vectors and gene-modified animals. (2) By using the molecular-biological tools which enable us to visualize information input sites (dendrites and cell body), we are studying the local circuit of the cerebral cortex and striatum. (3) Further, using the viral vectors that can visualize axon fibers very effectively, we are also examining the whole axonal arborization of single neurons in the thalamus and basal ganglia.

Takeshi Kaneko, M.D., Ph.D.Professor

Research and Education(1) Development of molecular-biological tools for the morphological study of the brain: We are now trying to develop many genetic tools for the analysis of neuronal circuit. The viral vectors expressing plasma membrane-targeted GFP has been developed to visualize neurons in a Golgi-stain-like manner. Furthermore, graduate students are producing genetically altered animals that express dendritic membrane-targeted GFP selectively in a particular subset of neurons. (2) Study of local circuitry in the cerebral cortex and striatum: Local neuronal circuitry is considered to be the basis of the higher functions executed by the brain. A graduate student is studying the cortical local connection of a pyramidal neuron to the corticothalamic neuron group, combining the intracellular staining technique with the retrograde dendrite-labeling method of the viral vector. Another graduate student is examining the local connection of a cortical interneuron to the corticospinal projection neuron group, using the whole cell recording/labeling technique in the genetically modified animals in which cortical interneurons are labeled with GFP. Furthermore, after generation of transgenic animals in which the dendrites of a particular set of cortical and striatal interneurons are labeled in a Golgi-stain-like fashion, we are now analyzing excitatory and inhibitory inputs to the particular set of interneurons on electron and confocal laser-scanning fluorescent microscopes. (3) Single neuron labeling study of thalamic and basal ganglia neurons: Using the viral vector that produces the plasma membrane-targeted GFP, we have recently reported the complete axonal arborization of thalamocortical and nigral dopaminergic neurons at the single neuron level. Graduate students and postdoctoral fellows are now examining other thalamocortical and thalamostriatal neurons in many thalamic subnuclei, and also studying projection neurons in the basal ganglia nuclei, such as the striatum, globus pallidus, subthalamic nucleus and substantia nigra.

Recent Publications1. Tanaka T, Kaneko T, Aoyagi T, Recurrent infomax generates cell assemblies, neuronal avalanches,

and simple cell-like selectivity. Neural Computation 21:1038-67, 2009 . 2. Kuramoto E, Furuta T, Nakamura KC, Unzai T, Hioki H, Kaneko T. Two types of thalamocortical

projections from the motor thalamic nuclei of the rat: A single neuron tracing study using viral vectors. Cerebral Cortex 19: 2065-77, 2009 .

3. Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F, Arai R, Kaneko T. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. The Journal of Neuroscience, 29: 444-53, 2009.

4. Furuta T, Kaneko T, Deschênes M. Septal neurons in barrel cortex derive their receptive field input from the lemniscal pathway. The Journal of Neuroscience 29: 4089-95, 2009.

5. Ohira K, Furuta T, Hioki H, Nakamura KC, Kuramoto E, Tanaka Y, Funatsu N, Shimizu K, Oishi T, Hayashi M, Miyakawa T, Kaneko T, Nakamura S. Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells. Nature Neuroscience, 13: 173-9, 2010.

6. Furuta T, Urbain N, Kaneko T, Deschênes M. Corticofugal control of vibrissa-sensitive neurons in the interpolaris nucleus of the trigeminal complex. The Journal of Neuroscience 30: 1832-38, 2010.

Morphological Brain ScienceProfessor : Takeshi Kaneko Associate Professor : Fumino Fujiyama Assistant Professor : Takahiro Furuta, Hiroyuki Hioki TEL : +81-75-753-4331 FAX : +81-75-753-4340 e-mail : [email protected] URL : http://www.mbs.med.kyoto-u.ac.jp/

Morphological Brain Science

- Basic Medicine (Core Departments) - Basic Neuroscience


In recent years, progress in various methods of research has opened the doors to revealing much about the integrative functions of the brain, such as emotion, consciousness, and the mind. However, there is still much to be learned about the brain. The brain is an organ, acquired in the course of evolution, for information processing, and it is a highly sophisticated system made up of over 100 billion intertwined neurons. It can do the work that not even the most advanced computer could possibly carry out. The study of the brain is not complete unless approached from both the biological (the hardware) and the computational (the software) angles. People proficient in all sorts of disciplines are invited to collaborate in exploring this ultimate theme.

Kenji Kawano, M.D., Ph.D.Professor

Research and EducationVarious techniques employed in neuroscience, such as molecular biology, neuroanatomy, and brain imaging techniques are constantly unfolding and reporting new findings. It is a rapidly advancing field. In our laboratory, we address the brain as an information processing system, and apply neurophysiological techniques to study the function of the intricate neural network that is behind human perception, planned action and thought. (1) We focus on visual tracking responses of the eyes to study the transformation of sensory to motor information. We have recorded neuronal activities in different parts of the brain while monkeys performed visual-oculomotor tasks. We analyzed the data using mathematical methods and revealed the role of the cerebral cortical area MST and cerebellum in controlling the ocular following response. To fully understand the function of the brain, we have found that simultaneously application of two approaches most effective. One is the analytical approach based on the biological properties of the neurons by electrophysiology, and the other is an integrative high level systems approach by computational neuroscience. We will continue to pursue this theme in studying higher brain functions. (2) The aim of another group is to elucidate neural mechanisms underlying visual attention. We examined neuronal activities in multiple cortical areas of macaque monkeys performing a visual search, and have revealed the hierarchical and integrative processing manner over multiple cortical areas.Education and training of young prospective researchers are also our primary concern. We have a comprehensive series of lectures for graduate school (master course) students and neuroscience seminars for graduate school (doctor course) students.

Recent Publications1. Inaba N, Miura K, Kawano K (2011) Direction and speed tuning to visual motion in cortical areas

MT and MSTd during smooth pursuit eye movements. J Neurophysiol. (in press). 2. Ogawa T, Komatsu H, (2010) Differential temporal storage capacity in the baseline activity of

neurons in macaque frontal eye field and area V4. J Neurophysiol. 103: 2433-45. 3. Miura K, Kobayashi Y, Kawano K. (2009) Ocular responses to brief motion of textured

backgrounds during smooth pursuit in humans. J Neurophysiol. 102:1736-47. 4. Ogawa T, Komatsu H. (2009) Condition-dependent and condition-independent target selection in

the macaque posterior parietal cortex. J Neurophysiol. 101:721-36. 5. Miura K, Sugita Y, Matsuura K, Inaba N, Kawano K, Miles FA (2008) The initial disparity

vergence elicited with single and dual grating stimuli in monkeys: evidence for disparity energy sensing and nonlinear interactions. J Neurophysiol. 100:2907-18.

❶ Information processing in the brain for ocular following response.

❷ Multidimensional visual search task and neuronal dynamics of bottom-up and top-down signals in visual area V4

❸ A set-up for a human oculomotor experiment.

❹ Staffs

Integrative Brain ScienceProfessor : Kenji Kawano Associate Professor : Tadashi Ogawa Assistant Professor : Takeshi Nishio, Kenichiro Miura TEL : +81-75-753-4675 FAX : +81-75-753-4486 e-mail : [email protected] URL : http://www.brain.med.kyoto-u.ac.jp/

Integrative Brain Science

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Auditory system has many marvelous capabilities. It can discriminate small difference of sound frequency, and it can identify the location of sound source in high precision. Although our nervous system is operating by using a clock of approximately 1 msec, our auditory system can detect a time difference of 10 μ(micro)sec or less. We are studying these capabilities of our nervous system for hearing, trying to understand the mechanisms how to calculate the interaural difference of time and intensity of sound, and then how to create the space map of hearing around us within the brain.

Harunori Ohmori, M.D., Ph.D.Professor

Research and EducationBarn owl can catch the prey in darkness, guided completely by hearing. Because of its preciseness on sound source localization, Barn owl is told to have a super sense of hearing. When the sound source moved in 1 degree in the azimuth plane, a small difference of sound travel time was created between two ears. It would be about 4 μ(micro)sec in the owl, and 2 μ(micro)sec in the chicken, and 10 μ(micro)sec in man; these differences are dependent on the size of head. Man and owl can detect this small difference of time. From the investigation how the accuracy of coincidence detection is achieved on the chicken nervous system for hearing, we found that the precise calculation of time difference was made by the fast synaptic interaction between sound signals originating in the left and the right ears. We can now predict some optimal condition in which even chicken could calculate the sound source localization as precisely as owl. In these studies to explore the neural mechanisms of hearing, we utilize various techniques of electrophysiology, morphology and molecular biology depending on the purpose of experiment.

Recent Publications1. Fukui I, Sato T and Ohmori H (2006). Improvement of phase information at low sound frequency

in nucleus magnocellularis of the chicken. Journal of Neurophysiology 96:642-651. 2. Kuba,H Ishii, MT and Ohmori,H (2006). Axonal site of spike initiation enhances auditory

coincidence detection. Nature 444:1069-1072. 3. Ishii, MT Nakashima, N and Ohmori,H (2007). Tytophan-scanning mutagenesis in the S1 domain

of mammalian HCN channel reveals residues critical for voltage-gated activation. Journal of Physiology Mar 1; 579 (pt2):291-301, 2007.

4. Nishino, Eri Yamada,R Kuba,H Hioki,H Furuta,T Kaneko,T and Ohmori, H (2008). Sound-Intensity-Dependent Compensation for the Small Interaural Time Difference Cue for Sound Source Localization. Journal of Neuroscience 28(28): 7153-7164.

5. Kuba, H and Ohmori,H (2009) Roles of axonal sodium channels in precise auditory time coding at nucleus magnocellularis of the chick. Journal of Physiology Jan 15: 587(Pt1): 87-100.

❶ Projection and terminal morphology of auditory nerve fibers in the Ncl. Magnocelluaris (NM) of chicken, a part of cochlear nucleus in birds. Shapes of nerve terminals are specialized in the graded manner, and are large calyx form in the high and small bouton form in the low frequency region. Neurons in NM extract the timing information of sound through this synapse formed by the auditory fiber, and then transmit it bilaterally to Ncl. Laminaris (NL).

❷ Neu rons i n NL rece i ve tempora l information of sound from bilateral NM and calculate the time difference between them. The shape of neuron is characteristic; extending many dendrites in two poles, and one axon emerges from the cell body (inset). These neurons are arranged in one layer in NL and work as precise coincidence detectors.

Physiology and Neurobiology (Physiology 1)Professor : Harunori Ohmori Associate Professor : Hiroshi Kuba Assistant Professor : Rei Yamada, Iwao Fukui TEL : +81-75-753-4351 FAX : +81-75-753-4349 e-mail : [email protected] URL : http://www.nbiol.med.kyoto-u.ac.jp

Physiology and Neurobiology (Physiology 1)

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The concept of pharmacology is being revolutionalized from classical discipline of description of drug actions to examining functions of biological molecules for effective drug invention. Our group is pursuing such a brand-new style of pharmacological approach while focusing on functions of prostaglandin receptors and Rho small G proteins. Such an approach requires integration of multi-level understanding from the molecular and cellular levels to the whole-system. We most welcome young enthusiastic people interested in physiology and medicine join our group regardless of their educational backgrounds.

Shuh Narumiya, M.D., Ph.D.Professor

Research and EducationOur goal is to understand physiological and pathological roles of prostaglandin receptors and Rho small G proteins not only at the molecular and cellular levels but also at the whole-system level. Collaborating with pharmaceutical companies, we also aim to develop drugs specifically targeting these molecules and their related signaling pathways for their potential clinical application. More specifically, in the field of prostaglandin receptors, while advancing our understanding of their actions in inflammation, immunity, fever and pain by using mice deficient with prostaglandin receptors, we are revealing their unexpected functions such as behavioral control under psychological and social stress. We are also paving the way for the clinical application of drugs acting on prostaglandin receptors for allergy. In the field of Rho small G proteins, we are challenging the central questions of cell biology including mechanisms for cell attachment, migration as well as cytokinesis. By generating mice deficient with Rho effectors, we are studying the system-level functions of Rho small G proteins such as those in structural formation and plasticity of the central nervous system. Y compound, a specific ROCK inhibitor we developed, is also considered for its potential clinical use. Therefore our laboratories are realizing a novel pharmacological approach integrating understandings at the molecular and cellular levels to those at the whole-system level. We are also interested in developing researchers with multidisciplinary scope of physiology and medicine, which are required for system-level science in the postgenome era.

Recent Publications1. Watanabe, S. et al. (2010) Rho and anillin-dependent control of mDia2 localization and function in

cytokinesis. Mol. Biol. Cell, 21, 3193-3204. 2. Esaki, Y. et al. (2010) Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune

encephalomyelitis. Proc. Natl. Acad. Sci. U. S. A., 107, 12233-12238. 3. Tanaka, Y. et al. (2009) Prostaglandin E receptor EP1 enhances GABA-mediated inhibition of

dopaminergic neurons in the substantia nigra pars compacta and regulates dopamine level in the dorsal striatum. Eur. J. Neurosci., 30, 2338-2346.

4. Oga, T. et al. (2009) Prostaglandin F2alpha receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta. Nat. Med., 15, 1426-1430.

5. Yao, C. et al. (2009) Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion. Nat. Med., 15, 633-640.

❶ Eight members of the p r o s t a n o i d r e c e p t o r family and structure of the thromboxane receptor.

❷ Act in stress f ibers in Swiss 3T3 fibroblasts and cytokinesis of HeLa cells.

❸ Lab personnels

Cell PharmacologyProfessor : Shuh Narumiya Associate Professor : Toshimasa Ishizaki, Takako Hirata (AK Project) Assistant Professor : Tomoyuki Furuyashiki, Daiji Sakata TEL : +81-75-753-4392 FAX : +81-75-753-4693 e-mail : [email protected] URL : http://www5.mfour.med.kyoto-u.ac.jp

Cell Pharmacology

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- Basic Medicine (Core Departments) - Basic Neusocience


The increases of lifestyle-related diseases, avian influenza and other infectious diseases, safety problems of the food including mad cow disease and so forth have occurred not only on a large scale in Japan but on a worldwide scale. As well in public health research, we study these problems from various viewpoints, and are carrying out research works about measures and solutions. In particular, we have worked with councils, municipalities and public health centers to discuss these public health problems and proposed measures to them. Moreover, about the measures against smoking which is a global problem, we have discussed about them in several countries. For this reason, having knowledge of medicine and /or the public health system in Japan are required for our researchers,as well as the ability of speaking English.

Toshitaka Nakahara, M.D., Ph.D.,M.P.HProfessor

Research and EducationOur department, whose basis is public health department of the medical school, deals with public health in the Faculty of Medicine and public health and international health in the School of Public Health. In education, we carry out in several programs, such as the public health in the faculty of medicine and public health, public health and welfare administration and health care administration in the School of Health Science. We also deal with core-curriculum, health policy and international health in the School of Public Health. We use the qualitative and quantitative analysis method and its fusion-technique, and the social-marketing-technique in research, focusing on health education for lifestyle-related diseases (hypertension, diabetes mellitus, hyperlipidemia, osteoporosis ) ,and measures against smoking, and HIV/AIDS. We analyze present condition, and are developing more effective and more efficient methods for them. Since in the field of public health, not only study but also practice is necessary, we cooperate with some councils, municipalities and prefectures to solve public health problems and we apply the results of our studies progressively. The measures against smoking which is one of the main causes of lifestyle-related diseases, not only in Japan but all over the world, has made them the main targets of our studies. We also held and national and international meetings( 62nd Annual meeting of Japanese Public Health Society, 2nd General Meeting of IUHPE-NPWP. 1st meeting of the Japanese Association of Smoking Control Science and, in 2008 7th annual meeting of International Society for the Prevention of Tobacco Induced Diseases). Now, besides studies on health education of lifestyle related diseases, we also carry out studies on the safety of foods,including measures against terrorism,research on public health and law, and sanitation, not only in Japan but overseas as well.

Recent Publications1. Current Japanese Tobbacco Consumption Situation. Toshitaka Nakahara, K. Satomura, S.

Iwanaga, R. Sakamoto, M. Noami, T. Takahashi Tobacco Counters Health, Volume 4, ISBN 81-7211-208-4, P.11-13 2005

2. Hospital's Measures against Passive Smoking. Ryota Sakamoto, Toshitaka Nakahara, Kazunari Satomura, Suketaka Iwanaga, Megumi Noami, Akihiko Kinugasa Tobacco Counters Health, Volume 4, ISBN 81-7211-208-4, P.23-27 2005

3. What is Necessary to Obey the FCTC in Japan. Kazunari Satomura, Toshitaka Nakahara, Suketaka Iwanaga, Ryota Sakamoto, Megumi Noami, Toru Takahashi Tobacco Counters Health, Volume 4, ISBN 81-7211-208-4, P.32-35 2005

4. Changes of Health Warning Labellings on Japanese Tobacco Packages Suketaka Iwanaga, Toshitaka Nakahara, Kazunari Satomura, Ryota Sakamoto, Megumi Nomai, Toru Takahashi

Tobacco Counters Health, Volume 4, ISBN 81-7211-208-4, P.36-38 2005 5. New approaches to public health education, research and practice Toshitaka Nakahara Raku-Yu 10

4-5 2006 6. Takashi Muto, Toshitaka Nakahara, Eun Woo Nam : Asian Perspectives and Evidence on Health

Promotion and Education. Springer 2011

❶ The 7th Annual Meeting of International Society for the Prevention of Tobacco Induced Diseases

❷ After The 19th Japanese Society of Health Education and Promotion

Public HealthProfessor : Toshitaka Nakahara Associate Professor : Kazunari Satomura Assistant Professor : Suketaka Iwanaga TEL : +81-75-753-4465 FAX : +81-75-753-4466 e-mail : [email protected]

Public Health

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- Basic Medicine (Core Departments) - Preventive Medicine


A high-quality draft sequence of the rat genome was reported in March, 2004. Considering the importance of the laboratory rat in medical research, our main research is focused on this species. Since fiscal year 2002, our institute ILA has been a core center for the rat of the National Bio Resource Project in Japan, and contributes to the promotion of biomedical science. We welcome postgraduate students who are interested in our project.

Tadao Serikawa, D.V.M., Ph.D.Professor

Research and EducationThe laboratory rat (Rattus norvegicus) is very useful to study prevention and treatment of human diseases, because of its suitable body size for manipulation and its physiology that is very similar to that of humans. Our research focus is the identification of causative genes of these rat models by means of genetic analysis. This approach can discover novel genes which are related to human diseases. We, now, intensively try to identify causative genes of the Noda Epileptic Rat (NER) which shows tonic-colonic seizures. Another research focus is to establish rat models of human diseases by “reverse-genetic” approaches. Recently, new technologies were established to create genetically-modified rats by ENU mutagenesis, zinc-finger nuclease, ES cells, and iPS cells. We have already developed rat modes of colon cancer, febrile seizure, epilepsy, and immune-deficiency. Our efforts aim to develop excellent rat models of human diseases and, by using these rat models, we intend to find pathological mechanisms of diseases and develop new methods to prevent and treat human diseases. The National Bio Resource Project - Rat grows to one of the largest resource center in the world and globally distributes high-quality rat strains to interested researchers.

Recent Publications1. A mutation in the gene encoding mitochondrial Mg2+ channel MRS2 results in demyelination in

the rat.Kuramoto T, Kuwamura M, Tokuda S, Izawa T, Nakane Y, Kitada K, Akao M, Guénet JL, Serikawa T. PLoS Genet. 7(1):e1001262, 2011

2. A missense mutation of the gene encoding voltage-dependent sodium channel (Nav1.1) confers susceptibility to febrile seizures in rats.Mashimo T, Ohmori I, Ouchida M, Ohno Y, Tsurumi T, Miki T, Wakamori M, Ishihara S, Yoshida T, Takizawa A, Kato M, Hirabayashi M, Sasa M, Mori Y, Serikawa T. J Neurosci, 30(16):5744-53, 2010

3. Generation of knockout rats with X-linked severe combined immunodeficiency (X-SCID) using zinc-finger nucleases. Mashimo T, Takizawa A, Voigt B, Yoshimi K, Hiai H, Kuramoto T, Serikawa T. PLoS One. 5(1):e8870, 2010

4. The STAR Consortium*, Saar K, Beck A, Bihoreau MT, Birney E, Brocklebank D, Chen Y, Cuppen E, Demonchy S, Dopazo J, Flicek P, Foglio M, Fujiyama A, Gut IG, Gauguier D, Guigo R, Guryev V, Heinig M, Hummel O, Jahn N, Klages S, Kren V, Kube M, Kuhl H, Kuramoto T, Kuroki Y, Lechner D, Lee YA, Lopez-Bigas N, Lathrop GM, Mashimo T, Medina I, Mott R, Patone G, Perrier-Cornet JA, Platzer M, Pravenec M, Reinhardt R, Sakaki Y, Schilhabel M, Schulz H, Serikawa T, Shikhagaie M, Tatsumoto S, Taudien S, Toyoda A, Voigt B, Zelenika D, Zimdahl H, Hubner N. SNP and haplotype mapping for genetic analysis in the rat. Nat Genet. 40(5):560-566, 2008

5. Aitman TJ, Critser JK, Cuppen E, Dominiczak A, Fernandez-Suarez XM, Flint J, Gauguier D, Geurts AM, Gould M, Harris PC, Holmdahl R, Hubner N, Izsvák Z, Jacob HJ, Kuramoto T, Kwitek AE, Marrone A, Mashimo T, Moreno C, Mullins J, Mullins L, Olsson T, Pravenec M, Riley L, Saar K, Serikawa T, Shull JD, Szpirer C, Twigger SN, Voigt B, Worley K. Progress and prospects in rat genetics: a community view. Nat Genet. 40(5):516-522, 2008

6. Mashimo T, Yanagihara K, Tokuda S, Voigt B, Takizawa A, Nakajima R, Kato M, Hirabayashi M, Kuramoto T, Serikawa T. An ENU-induced mutant archive for gene targeting in rats. Nat Genet. 40(5):514-515, 2008

❶ Lab Staff ❷ X-SCID rats generated

by zinc-finger nuclease technology (left-upper : thymic deficiency, right-lower: xenotransplantation of human ovarian cancer cells)

❸ National Bio Resource Project - Rat

Institute of Laboratory Animals (Laboratory Animal Science)Professor : Tadao Serikawa Associate Professor : Takashi Kuramoto, Tomoji Mashimo Senior Lecturer : Taketo Kaneko TEL : +81-75-753-4489 FAX : +81-75-753-4409 e-mail : [email protected] URL : http://www.anim.med.kyoto-u.ac.jp/

Laboratory Animal Science

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- Basic Medicine (Core Departments) - Institute of Laboratory Animals


Approximately 3% of newborn babies suffer from congenital anomalies (birth defects), which is a serious burden for patients and their families. Many congenital anomalies are assumed to be caused by the interaction of gene mutations and environmental factors, but the etiology and pathogenetic mechanisms remain to be clarified for most birth defects. In our laboratory, interdisciplinary research approaches are being undertaken to elucidate the causes and pathogenesis of birth defects and to attempt to identify some preventive measures.

Keiji Tamaki, M.D.,Director and Professor

Research and EducationThis Center has the largest collection of human embryo specimens in the world comprising of over 44,000 therapeutic abortuses. Most of the specimens are between the 3rd and 8th week following fertilization, which is the critical period of teratogenesis. In the Kyoto Collection of Human Embryos, an appreciable number of malformed embryos are included, which provide a unique opportunity to study the early stages of abnormal morphogenesis. A variety of research projects are at present being undertaken on the embryo collection.

1) Pathological and molecular cell biology analyses of human malformationsAmong the early embryo population, many malformations have been demonstrated to be present several times more frequently than in the newborn population. We are in the process of investigating the early pathogenetic process of various malformations, such as neural tube defects, holoprosencephaly and oral clefts. Where possible, the genes of abnormal embryos are analyzed by molecular methods.

2) 3D database of human prenatal developmentUsing the magnetic resonance (MR) microscope, a 3D database of normal and abnormal human embryos is in the process of being established (http://bird.cac.med.kyoto-u.ac.jp). This database will be useful not only in the study of human embryology but also for future gene mapping studies in human development. This is a collaborative research with Prof. Katsumi Kose of Tsukuba University and has been funded by the "Bioinformatics R & D (BIRD)" Project of the Japan Science and Technology Agency (2005-2010).

3) Genetic epidemiological study of the etiology of human birth defectsGenetic epidemiological studies can be undertaken more efficiently in the embryo population than in newborns, since the prevalence rates of various malformations are much higher in embryos. To date, we have identified the association between neural tube defects and maternal hyperthermia and also clarified that more than 90% of embryos with serious malformations are spontaneously aborted early in the gestation period.

4) Experimental studies of abnormal morphogenesisThe pathogenetic mechanisms and preventive measure of birth defects are being investigated using in vivo and in vitro experimental systems.

5) Normal development of human embryosWe have identified some important facts about human morphogenesis, which have corrected some established theories of development. These include the following: (a) neural tube closure in human embryos is initiated at multiple sites; and (b) apoptosis or “programmed cell death” is not a necessary prerequisite for palate fusion.

6) Development of a multimedia tutorial program for human embryologyUsing the human embryo data, we are developing a novel tutorial program of human embryology with the aid of computer graphics and other multimedia technologies. This is a collaboration with the Academic Center for Computing and Media Studies of Kyoto University.

Recent Publications1. Yamada S, Lee ES, Samtani RR, Lockett E, Uwabe C, Shiota K, Anderson SA, Lo CW.

Developmental atlas of the early first trimester human embryo. Dev Dyn, 2010 Jun;239(6):1585-95.

2. Ayman A, Funatomi T, Mihon M, Elnomery Z, Okada T, Togashi K, Sakai T, Yamada S. New region growing segmentation technique for MR images with weak boundaries. IEICE Technical Report 2010 Nov;110:71-76.

3. Bleyl SB, Saijoh Y, Bax NA, Gittenberger-de Groot AC, Wisse LJ, Chapman SC, Hunter J, Shiratori H, Hamada H, Yamada S, Shiota K, Klewer SE, Leppert MF, Schoenwolf GC. Dysregulation of the PDGFRA gene causes inflow tract anomalies including TAPVR: integrating evidence from human genetics and model organisms. Hum Mol Genet. 2010 Apr 1;19(7):1286-301. Epub 2010 Jan 13.

4. Shiota K, Yamada S. Early pathogenesis of holoprosencephaly. Am J Med Genet C Semin Med Genet, 2010 Jan;154(1):22-28.

5. Dhanantwari P, Lee E, Krishnan A, Samtani R, Yamada S, Anderson S, Lockett E, Donofrio M, Shiota K, Leatherbury L, Lo CW. Human cardiac development in the first trimester: a high-resolution magnetic resonance imaging and episcopic fluorescence image capture atlas. Circulation. 2009 Jul 28;120(4):343-51.

❶ An 8-week human embryo in the amniotic sac ❷ Computer graphic images of human embryonic development between the 4th and 8th

weeks following fertilization ❸ A 7-week embryo and the 3D reconstructed image of its brain ❹ MR images of 6-, 7- and 8-week embryos ❺ Sectional MR images of a 7-week embryo ❻ Histology lab with serial histological sections of 1,000 embryo cases

Congenital Anomaly Research CenterProfessor : Keiji Tamaki Associate Professor : Shigehito Yamada TEL : +81-75-753-4345 FAX : +81-75-753-4621 URL : http://www.cac.med.kyoto-u.ac.jp/

Congenital Anomaly Research Center

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- Basic Medicine (Core Departments) - Congenital Anomaly Research Center


Study of human diseases based on genetic information in the human genome is one of the most important subjects in the Post Genome Project. In particular, to overcome human multigenetic disorders, it is essential to perform trans-ethnic genetic analyses of human genome variations. In our laboratory, we perform SNP identification and genotyping of candidate genes of multigenetic diseases using DNA samples of patients and control subjects from different ethnic origins. We also work on the construction of a comprehensive SNP database of different multigenetic diseases which integrates genetic and clinical information using the latest bioinformatic and statistical genetic tools. We try to establish a new generation genome variation-based genomic strategy which will directly linked to clinical research and therapeutics.

Fumihiko Matsuda, Ph.D.Professor

Research and EducationWe have established an extensive international collaboration for ‘Genomic Epidemiology of Human Multigenetic Disorders’ with Centre National de Genotypage (CNG) in France. We focus on diseases related to the immune system such as Rheumatoid Arthritis, Lupus, Hyperthyroidism and AIDS, and those in which DNA repair mechanism is involved such as cancer. We have started a systematic SNP identification using a standard panel of DNA samples from multiple ethnic groups (Caucasians, Japanese, Africans, Thai). Based on the SNP catalog obtained, we undertake a large-scale case/control study by genotyping SNPs on an epidemiological scale (sample scale of >1,000 individuals). Results are deposited in a disease-based genetic database which contains information of genes and their genetic variations combined with patient’s clinical information. Extensive statistical analyses is performed using a variety of statistical programs developed from joint research with CNG and The Rockefeller University in U.S.A. Comparison of genotypes between patients and controls among different ethnicities leads to the identification of disease-specific and ethnicity-specific genome variations. Annotated data will be made available to the scientific community as basic genetic information of diseases for future development of diagnostics and individual-based therapy (taylor-made medicine).

Recent Publications1. SEARCH Collaborative Group, Link, E., Parish, S., Armitage, J., Bowman, L., Heath, S., Matsuda,

F., Gut, I., Lathrop, M. and Collins, R. (2008) SLCO1B1 variants and statin-induced myopathy--a genomewide study. N. Engl. J. Med. 359, 789-799.

2. McKay, J.D. et al. (2008) Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404-1406 3. Wada, M., Marusawa, H., Yamada, R., Nasu, A., Osaki, Y., Kudo, M., Nabeshima, M., Fukuda, Y.,

Chiba, T. and Matsuda, F. (2009) Association of genetic polymorphisms with interferon-induced haematologic adverse effects in chronic hepatitis C patients. J. Viral. Hepat. 16, 388-396.

4. Nakanishi, H., Yamada, R., Gotoh, N., Hayashi, H., Yamashiro, K., Shimada, N., Ohno-Matsui, K., Mochizuki, M., Saito, M., Iida, T., Matsuo, K., Tajima, K., Yoshimura, N. and *Matsuda, F. (2009) A Genome-Wide Association Analysis Identified a Novel Susceptible Locus for Pathological Myopia at 11q24.1. PLoS Genetics Epub 2009 Sep 25.

5. Takahashi, M., Saenko, V. A., Rogounovitch T. I., Kawaguchi, T., Drozd, V. M., Takigawa-Imamura, H., Natallia M. Akulevich, N. M., Ratanajaraya, C., Mitsutake, N., Takamura, N., Danilova, L. I., Lushchik, M. L., Demidchik, Y. E., Heath, S., Yamada, R., Lathrop, M., Matsuda, F. and Yamashita, S. (2010) The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Hum. Mol. Genet. Mar 30. [Epub ahead of print]

6. Nalpas, B., Lavialle-Meziani, R., Plancoulaine, S., Jouanguy, E., Nalpas, A., Munteanu, M., Charlotte, F., Ranque, B., Patin, E., Heath, S., Fontaine, H., Vallet-Pichard, A., Pontoire, D., Bourlière, M., Casanova, J. L., Lathrop, M., Bréchot, C., Poynard, T., Matsuda, F., Pol, S. and Abel, L. (2010) Interferon-γ receptor 2 gene variants are associated with liver fibrosis in patients with chronic hepatitis C infection. Gut. In the press

❶ Laboratry members

Human Disease Genomics(Center for Genomic Medicine)Professor : Fumihiko Matsuda Associate Professor : Hiroshi Kadotani Associate Professor (Industry-Academia Collaboration) : Yoshiki Murakami Assistant Professor : Meiko Takahashi TEL : +81-75-753-4661 FAX : +81-75-753-9314 e-mail : [email protected] URL : http://www.genome.med.kyoto-u.ac.jp/

Human Disease GenomicsCenter for Genomic Medicine

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- Basic Medicine (Core Departments) - Genome Epidemiology


More than 20,000 genes are there in the human genome. Comparing to the annotation of genes, how their expression is regulated are largely unknown. Moreover, identification of these regulatory regions in the genome seems to be very important for molecular medicine because mutations in these regions might be responsible for many diseases. Our goal is to understand the mechanisms of gene regulation in genomic scale by bioinformatics approaches.

Mikita Suyama Ph.DAssociate Professor

Research and EducationToday, more than 40 genomic sequences of various vertebrates are available, and comparative genome analyses is necessary to understand the changes in genomic structures and to identify functional regions. The main focus of our group is to get most insights into the regulation of gene expression, which may cause some diseases, by using bioinformatics means. The current research topics are (1) identification of cis-regulatory elements for transcription and splicing, (2) comparative genome analyses to understand gene duplications and genome rearrangements, (3) genome informatic analysis of sex differences, and (4) gene expression in cancer tissues. With the progress of high-throughput analyses, such as microarrays and next-generation sequence technologies, interpretation of the data is not possible without computational analyses. We will incorporate such heterogeneous data together with the sequence data into the genome-wide functional analyses.

M a s s i v e d a t a a n a l y s i s i s n o t o n l y f o r bioinformaticians, but the researchers working at the bench are also required to master to use some basic tools and databases. To support those researchers, we provide them with the bioinformatics expertise necessary for the genome sequence analyses and the high-throughput data analyses.

An interactive process between experimental molecular biologists and bioinformaticians is necessary to fully facilitate genome data and high-throughput data. Such process includes feedback-loop between hypothesis making and experimental verification. Therefore, we will also actively collaborate with others to get much further insights into molecular medicine.

Recent Publications1. Suyama M, Harrington ED, Vinokourova S, von Knebel Doeberitz M, Ohara O, and Bork P, A

network of conserved co-occurring motifs for the regulation of alternative splicing, Nucleic Acids Res. 38:7916-7926, 2010.

2. Iizuka Y, Okuno T, Saeki K, Uozaki H, Okada S, Misaka T, Sato T, Toh H, Fukayama M, Takeda N, Kita Y, Shimizu T, Nakamura M, and Yokomizo T, Protective role of the leukotriene B4 receptor BLT2 in murine inflammatory colitis, FASEB J. 24:4678-4690, 2010.

3. Soldà G, Suyama M, Pelucchi P, Boi S, Guffanti A, Rizzi E, Bork P, Tenchini ML, and Ciccarelli FD, Non-random retention of protein-coding overlapping genes in Metazoa, BMC Genomics 9:174, 2008.

4. Suyama M, Harrington E, Bork P, and Torrents D, Identification and analysis of genes and pseudogenes within duplicated regions in the human and mouse genomes, PLoS Comput. Biol. 2:e76, 2006.

5. Suyama M, Torrents D, and Bork P, PAL2NAL: robust conversion of protein sequence alignments into the corresponding codon alignments, Nucleic Acids Res. 34:W609-W612, 2006.

❶ A genome sequence alignment and a cis-element conserved among mammals.

❷ Microarray analysis of differentially expressed genes in inflammatory colitis.

Genome Informatics(Center for Genomic Medicine)Associate Professor : Mikita Suyama Assistant Professor : Tetsuya Sato TEL : +81-75-753-4383 FAX : +81-75-753-4382 e-mail : [email protected]

Genome InformaticsCenter for Genomic Medicine

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- Basic Medicine (Core Departments) - Center for Genomic Medicine


Topics concerning medical education have currently become important issues for our community.The traditional style of medical education has mainly been carried out through the efforts of individual departments of a medical school. Nowadays, however, it is impossible to provide an appropriate medical education without coordination of the efforts of individual sections. Therefore, the Center for Medical Education has been established at Kyoto University to play a central role in the promotion of modern medical education.

Research and EducationThe Center for Medical Education at Kyoto University is not one of the departments in the medical school. It has been established to promote medical education across the faculty, rather than to facilitate specific research or education carried out by individual departments.

Center is continuing the revision of medical education system of Kyoto University. Particularly recent activity has been focused to the reform of the framework of undergraduate clinical training course. With cooperation of many hospitals the course has been reformed as a clerkship-based pathway. Making e-learning systems we are now establishing the e-campus among all teachers and students. Improvement of postgraduate education is also one of missions of this center. We cooperate with the Education Center of Kyoto University Hospital in promoting resident education. For example faculty development of mentors for residents is one of main tasks for our center. We also support carrier planning of residents and students.

In addition to improving the system of medical education, the center is also engaged in development of learning program, such as a new basic course in Medical English, and a practical resuscitation clinical program for treatment of sudden cardiac arrest patients.

Recent Publications1. Hamasu S, Morimoto T, Kuramoto N, Horiguchi M, Iwami T, Nishiyama C, Takada K, Kubota

Y, Seki S, Maeda Y, Sakai Y, Hiraide A. Effects of BLS training on factors associated with attitude toward CPR in college students. Resuscitation 2009;80:359-364.

2. Kuramoto N, Morimoto T, Kubota Y, Maeda Y, Seki S, Takada K, Hiraide A. Public perception and willingness to perform bystander CPR in Japan. Resuscitation 2008;79:475-481

3. Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, Jinnouchi H, Sugiyama S, Saito Y; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008;300:2134-41.

❶ Core Members ❷ Center for Medical

Education located in the building D

Medical Education(Center for Medical Education)Senior Lecturer : Takeshi Morimoto, (Yuko Maeda: Human Health Science

Research Fields ) Assistant Professor : Mio Sakuma School Affairs Staff : Susumu Seki Assistant Teaching Staff : Kaori Takada secretary : Makiko Ohtorii, Ai Mizutani, Mika Sakai Office Assistant : Izumi Miki TEL : +81-75-753-9338 FAX : +81-75-753-9339 e-mail : [email protected] URL : http://plaza.umin.ac.jp/~cme/

Medical EducationCenter for Medical Education

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- Basic Medicine (Core Departments) - Center for Medical Education


We have been studying molecular mechanisms controlling development and function of lymphocytes. Currently we are addressing two important questions: 1) How antibody diversity is controlled by AID, a putative RNA-editing enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM), 2) How PD-1 deficiency leads to development of autoimmune diseases.

Tasuku Honjo, M.D., Ph.D.Professor

Research and Education“The mechanism of antibody memory”The use of vaccination to prevent infectious diseases has made profound and enduring impacts on human welfare since it was pioneered by Jenner in 1796. Extensive studies on immunoglobulin structure and function established that effective vaccination depends on the generation of antigen-specific antibody ‘memory’ characterized by two modifications of the immunoglobulin, namely class switching in the heavy-chain constant region, and an increased affinity for antigen in the variable region.In 1978, we proposed and subsequently proved that class switch is mediated by recombination with dynamic excision of genomic fragments. In 2000, we discovered activation-induced cytidine deaminase (AID), which is responsible for DNA cleavage to initiate both CSR and SHM. Surprisingly, AID mutates not only the antibody gene, but also protooncogenes. Whether or not AID induced in non-lymphoid cells by viral infection causes genomic alterations leading to cancer is a big question in the field. We have recently found that topoisomerase 1 (Top1) is the enzyme that initiates CSR and SHM by cleaving S and V region, respectively. In addition, AID reduces the amount of Top1, inducing the target DNA structural change, which causes the irreversible cleavage by Top1. Furthermore, the transcription coupled nucleosomal reassembly is critical for this Top1-mediated DNA cleavage during CSR and SHM. Furthermore, we also investigate the function of Programmed cell-death-1 (PD-1), which was isolated in this laboratory and shown to be the key molecule in regulation of lymphocyte activity including tolerance. PD-1 plays critical roles in anti-cancer immunity and autoimmunity. The aim of our research is to contribute to human welfare through regulation of immune responses, elucidation of tumorigenesis and its prevention by studying the function of AID and PD-1. In our lab, highly motivated students and postdocs are collaboratively working to elucidate fundamental questions in immunology. We educate them to be independent and sophisticated scientists who are not only specialized in biochemical and immunological experimental techniques, but also have global view of life science.

Recent Publications1. Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y. and Honjo, T. “Class switch

recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.” Cell (2000) 102(5):553-63.

2. Muramatsu, M., Nagaoka, H., Shinkura, R., Begum, N. A. and Honjo, T. “Discovery of activation-induced cytidine deaminase, the engraver of antibody memory.” Adv. Immunol. (2007) 94:1-36.

3. Kobayashi, M., Aida, M., Nagaoka, H., Begum, N. A., Kitawaki, Y., Nakata, M., Stanlie, A., Doi, T., Kato, L., Okazaki, I., Shinkura R., Muramatsu, M., Kinoshita, K. and Honjo, T. “AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination.” Proc. Natl. Acad. Sci. USA (2009) 106:22375-80.

4. Stanlie, A., Aida, M., Muramatsu, M., Honjo, T. and Begum, N. A. “Histone3 lysine4 trimethylation regulated by the facilitates chromatin transcription complex is critical for DNA cleavage in class switch recombination.” Proc. Natl. Acad. Sci. USA (2010) 107: 22190-5.

5. Wei, M., Shinkura, R., Doi, Y., Maruya, M., Fagarasan, S. and Honjo, T. “Knock-in mice carrying a somatic hypermutation-defective Aicda mutation have impaired gut homeostasis and compromised mucosal defense.” Nat. Immunol. (2011) 12: 264-70.

❶ C l a s s S w i t c h R e c o m b i n a t i o n research group

❷ A I D e n g r a v e s antibody memory on the genome

❸ PD-1 research group ❹ PD-1 deficient mice

develop autoimmune n e u r o p a t h y d u e t o t h e b r e a k a g e o f l y m p h o c y t e tolerance

Immunology and Genomic MedicineProfessor : Tasuku Honjo Associate Professor : Nasim Begum, Maki Kobayashi Assistant Professor : Shunsuke Chikuma TEL : +81-75-753-4371 FAX : +81-75-753-4388 e-mail : [email protected] URL : http://www2.mfour.med.

Immunology and Genomic MedicineContributed Chairs

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- Basic Medicine (Core Departments) - Immunology and Genomic Medicine


Diversity is a fundamental feature of biology. Recent developments in genomics and related research fields with massive data have provided great opportunities to investigate biological diversity. The concept of health and diseases is an aspect of phenotypic heterogeneity itself, which means medical approach to the diversity is important. Statistical genetics is the study to understand biological diversity by expressing the diversity by combining genetic and environmental components with mathematical methods. Although it has a long and sound history since Gregor Johann Mendel, there are few laboratories titled “statistical genetics” in Japan. This laboratory in graduate school of medicine, Kyoto University, has just started in August, 2009. Another feature of statistical genetics is that it is becoming more and more interdisciplinary encompassing mathematics, statistics, information science, computer science, genetics, molecular biology and medicine and therefore you can start statistical genetics from any one of these basic fields.

Yamada, Ryo M.D., Ph.D.Professor

Research and EducationOur study goals are development of new data-mining methods for genetic polymorphisms and also assistance of data-mining processes of collaborators. We mainly target medically important phenotypes such as diseases and we are also interested in the heterogeneity in human phenotypes itself. Our laboratory does not perform biological experiments and when we analyze real data, they are provided by collaborators. We consider collaborations with data-producing laboratories very important. The structure of genetic polymorphisms is characterized by its very high dimension and small number of discrete categories of individual dimension, two or four. We believe it would be useful to utilize these features in development of new data-mining methods, although it is not mandatory. It would be a good idea to apply some data-mining strategies, that are in use or are being studied in other data-mining research fields, into our research field. It would also be important to attempt to apply more basic theories or technologies into our data-mining that are not conventionally used in other data-mining fields either. In case where basic theories or technologies are applied to our field, the above-mentioned features of data structure of polymorphisms would give good insights in the studies. Statistical genetics is interdisciplinary covering mathematics, statistics, information science, computer science, genetics, molecular biology and medicine. We will support anybody to use resources inside and/or outside of Kyoto University to master the details of these related fields.

Recent Publications1. Yamada R, Okada Y. An optimal dose-effect mode trend test for SNP genotype tables. Genet

Epidemiol. 2009 33(2):114-27 2. Suzuki A, Yamada R, Kochi Y, Sawada T, Okada Y, Matsuda K, et al. Functional SNPs in

CD244 increase the risk of rheumatoid arthritis in a Japanese population. Nat Genet. 2008 Oct;40(10):1224-9.

3. Yamamoto K, Yamada R. Lessons from a Genomewide Association Study of Rheumatoid Arthritis. N Engl J Med. 2007 September 20, 2007;357(12):1250-1.

4. Yamada R, Matsuda F. A novel method to express SNP-based genetic heterogeneity, Psi, and its use to measure linkage disequilibrium for multiple SNPs, D(g), and to estimate absolute maximum of haplotype frequency. Genet Epidemiol. 2007 Nov;31(7):709-26.

5. Cha PC, Yamada R, Sekine A, Nakamura Y, Koh CL. Inference from the relationships between linkage disequilibrium and allele frequency distributions of 240 candidate SNPs in 109 drug-related genes in four Asian populations. J Hum Genet. 2004;49(10):558-72.

❶ Statistical tests in genetic epidemiology requires much lower type-1 error threshold, which brings a new problem in discrepancy between asymptotic tests and exact tests. The figure draws the discrepancy in geometric expression.

❷ Neighboring loci make haplotypes, combination types of single alleles. Two dichotomous loci make four haplotypes, which are placed in three-dimensional space and chronological changes in haplotype frequency is displayed in the space.

❸ Haplotypes are expressed as strings of 0 and 1. Genetic distance among them can be defined with number of recombinations required. For this purpose, the concept of runs is useful.

❹ This figure is two-dimensional drawing of higher-dimensional cubes. Also they are graphs of lattices, which represent relation among the elements of a power set. It is useful to handle haplotypes, strings of 0 and 1, with these tools in discrete mathematic for development of methods of data mining.

❺ A part of an article.

Statistical Genetics(Center for Genomic Medicine)Professor : Yamada, Ryo M.D., Ph.D. TEL : +81-75-753-9470 FAX : +81-75-753-9284 e-mail : [email protected].

ac.jp URL : http://www.genome.med.kyoto-u.ac.jp/

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Statistical GeneticsCenter for Genomic Medicine

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- Basic Medicine (Core Departments) - Center for Genomic Medicine


Hematology is one of the areas in which active interactions and mutual stimulations between clinical medicine and basic science have been producing remarkable progress. We are trying to obtain deeper insights into mechanisms of and develop effective treatments for various hematological diseases, with a motto, “from bedside to bench, from bench to bedside”.

Akifumi TakaoriProfessor

Research and EducationFor cure of hematological malignancies and infectious diseases, we are engaged in several research projects of both basic and clinical approaches. Ongoing clinical research projects are as follows: 1. functional analysis of dendritic cells and its application to the immunotherapy of hematological malignancies, and 2. cell-mediated immunotherapy for hematological malignancies including adult T-cell leukemia using hematopietic stem cell transplantation. Basic approaches to hematological and infectious diseases include: 1. functional analysis of phagocytes and other cells involved in the innate and acquired immune systems, 2. analysis of the function and expression of molecules related to iron metabolism, 3. research on the tumorigenesis and pathology of various hematological malignancies including malignant lymphoma, adult T-cell leukemia and MDS/MPD, and 4. elucidation of the mechanisms by which HIV-1 Vif and an antiviral host factor, APOBEC3G, regulate the infectivity of HIV-1. Motivations for these basic research projects have also been arisen during our daily clinical work. We are making efforts to keep pace with rapid advances in hematology, and wish to contribute much to its further progress.

Recent Publications1. Hirai, M., Kadowaki, N., Kitawaki, T., Fujita, H., Takaori-Kondo, A., Fukui, R., Miyake, K.,

Maeda, T., Kamihira, S., Miyachi, Y. & Uchiyama, T. (2011). Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis. Blood 117, 500-9.

2. Izumi, T., Io, K., Matsui, M., Shirakawa, K., Shinohara, M., Nagai, Y., Kawahara, M., Kobayashi, M., Kondoh, H., Misawa, N., Koyanagi, Y., Uchiyama, T. & Takaori-Kondo, A. (2010). HIV-1 viral infectivity factor interacts with TP53 to induce G2 cell cycle arrest and positively regulate viral replication. Proc Natl Acad Sci U S A 107, 20798-803.

3. Hishizawa, M., Kanda, J., Utsunomiya, A., Taniguchi, S., Eto, T., Moriuchi, Y., Tanosaki, R., Kawano, F., Miyazaki, Y., Masuda, M., Nagafuji, K., Hara, M., Takanashi, M., Kai, S., Atsuta, Y., Suzuki, R., Kawase, T., Matsuo, K., Nagamura-Inoue, T., Kato, S., Sakamaki, H., Morishima, Y., Okamura, J., Ichinohe, T. & Uchiyama, T. (2010). Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study. Blood 116, 1369-76.

4. Yamashita, K., Miyoshi, T., Arai, T., Endo, N., Itoh, H., Makino, K., Mizugishi, K., Uchiyama, T. & Sasada, M. (2008). Ozone production by amino acids contributes to killing of bacteria. Proc Natl Acad Sci U S A 105, 16912-7.

5. Yamamoto, R., Nishikori, M., Kitawaki, T., Sakai, T., Hishizawa, M., Tashima, M., Kondo, T., Ohmori, K., Kurata, M., Hayashi, T. & Uchiyama, T. (2008). PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 111, 3220-4.

6. Shirakawa, K., Takaori-Kondo, A., Yokoyama, M., Izumi, T., Matsui, M., Io, K., Sato, T., Sato, H. & Uchiyama, T. (2008). Phosphorylation of APOBEC3G by protein kinase A regulates its interaction with HIV-1 Vif. Nat Struct Mol Biol 15, 1184-91.

❶ Immunohistochemical detection of PD-1 ligands in Hodgkin/Reed-Sternberg cells. (A) H&E, (B) CD30, (C) B7-H1, (D) B7-DC.

❷ Vif induces G2 cell cycle arrest in the presence of p53.

❸ Bortezomib inhibits trafficking of TLR9, but not of Unc93b, f rom the ER to endolysosomes induced by CpG ODN. (A, B) TLR9: green, lysosome: red. (C, D) Unc93B: green, lysosome: red.

Hematology and OncologyProfessor : Akifumi Takaori Associate Professor : Norimitsu Kadowaki Senior Lecturer : Hiroshi Kawabata, Kouhei Yamashita, Assistant Professor : Tadakazu Kondo, Momoko Nishikori, Masayuki Kobayashi, Masakatsu Hishizawa, Toshio Kitawaki, Keisuke Shindo TEL : +81-75-751-3150 FAX : +81-75-751-3201 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Hematology and Oncology

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- Clinical Medicine (Core Departments) - Internal Medicine


Recent studies demonstrate that not only classical endocrine organs but also virtually every tissue and organ possess the endocrine function. Based on this new concept of endocrinology and metabolism, we, the members of Department of Medicine and Clinical Science (Endocrinology and Metabolism) are focusing upon the diseases of endocrinology and metabolism, especially Metabolic Syndrome, which is so-called “life style-related diseases,” such as obesity, diabetes mellitus, hypertension and hyperlipidemia, and is the cluster of risk factors for atherosclerosis. We are investigating the pathogenesis of the syndrome and its complications, and performing translational research for the development of new therapeutic strategies.

Kazuwa Nakao, M.D., Ph.D.Professor

Research and EducationDepartment of Medicine and Clinical Science (Endocrinology and Metabolism) was founded in 1899 and has the history more than 110 years. Since 1992, under the supervision of Dr. Kazuwa Nakao, Professor and Chairman, the members of the department are engaged in the research activity aiming at the establishment of frontier medicine, in addition to the investigation on classical endocrine and metabolic diseases. Our goal is to achieve the elucidation of pathogenesis and the prevention of “life style-related diseases,” such as obesity, diabetes mellitus, hypertension, and their complications, and to develop new therapeutic strategies. In education and clinical services, our department is devoted to fostering expert doctors for endocrinology and metabolism and related fields, who can perform high quality and up-to-date diagnostic procedures and treatments. Furthermore, based upon the characteristics of endocrinology and metabolism to approach the maintenance of internal milieu, we aim at training “Physician Scientist” who can evaluate the patient as a whole and grasp the whole picture of pathophysiology the patient exhibits. Recently, as Japanese life-style is being westernized, Metabolic Syndrome, the cluster syndrome of obesity, diabetes mellitus, hypertension and hyperlipidemia, and its complications have been emphasized as an important social issue. We therefore focus especially upon this medical field and do comprehensive and advancing medical practice. In research activities, in order to achieve translational research which links basic research with clinical applications, we are performing molecular medical approach with molecular biology, molecular genetics and developmental biology to elucidate the pathogenesis and develop new therapeutic methods in the field. We, actually, have succeeded in achieving the clinical application of new hormones, natriuretic peptides, secreted from the cardiovascular organs, which have long been considered to be the pump or the vessel for circulation, and leptin, secreted from the adipose tissue, which is believed as the mere storage tissue for energy. We are also performing the research project of vascular regeneration medicine for vascular complications of the life style-related diseases, using human embryonic stem (ES) cells and iPS cells, as one of the first research groups in Japan.

Recent Publications1. T. Tanaka, H. Masuzaki, S. Yasue, K. Ebihara, T. Shiuchi, T. Ishii, N. Arai, M. Hirata, H.

Yamamoto, T. Hayashi, K. Hosoda, Y. Minokoshi, and K. Nakao. Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet. Cell Metab. 5: 395-402, 2007.

2. J. Fujikura, K. Hosoda, H. Iwakura, T. Tomita, M. Noguchi, H. Masuzaki, K. Tanigaki, D. Yabe, T. Honjo, and K. Nakao. Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas. Cell Metab. 3: 59-65, 2006.

3. A. Yasoda, Y. Komatsu, H. Chusho, T. Miyazawa, A. Ozasa, M. Miura, T. Kurihara, T. Rogi, S. Tanaka, M. Suda, N. Tamura, Y. Ogawa, and K. Nakao. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat. Med. 10: 80-86, 2004.

4. K. Kuwahara, Y. Saito, M. Takano, Y. Arai, S. Yasuno, Y. Nakagawa, N. Takahashi, Y. Adachi, G. Takemura, M. Horie, Y. Miyamoto, T. Morisaki, S. Kuratomi, A. Noma, H. Fujiwara, Y. Yoshimasa, H. Kinoshita, R. Kawakami, I. Kishimoto, M. Nakanishi, S. Usami, Y. Saito, M. Harada, and K. Nakao. NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function. EMBO J. 22: 6310-6321, 2003.

5. K. Yamahara, H. Itoh, T. Chun, Y. Ogawa, J. Yamashita, N. Sawada, Y. Fukunaga, M. Sone, T. Yurugi-Kobayashi, K. Miyashita, H. Tsujimoto, H. Kook, R. Feil, D. L. Garbers, F. Hofmann, and K. Nakao. Significance and therapeutic potential of natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration. Proc. Natl. Acad. Sci. USA, 100: 3404-3409, 2003.

6. J. Yamashita, H. Itoh, M. Hirashima, M. Ogawa, S. Nishikawa, T. Yurugi, M. Naito, K. Nakao, and S. Nishikawa. Flkl-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 408: 92-96, 2000.

Medicine and Clinical ScienceProfessor : Kazuwa Nakao Associate Professor : Masashi Mukoyama Senior Lecturer : Naohisa Tamura, Koichiro Kuwahara Assistant Professor : Masakatsu Sone, Naotetsu Kanamoto, Junji Fujikura, Yasuaki Nakagawa, Masako Miura, Toru Kusakabe Associate Professor (Special Appointment) : Kiyoshi Mori,Toshio nishikimi Lecturer (Special Appointment) : Masato Kasahara, Akihiro Yasoda Assistant Professor (Special Appointment) : Hideki Yokoi, Licht Miyamoto, Yuji Yamamoto, Hideyuki Kinoshita TEL : +81-75-751-3168 FAX : +81-75-761-1195 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~med2/

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Medicine and Clinical Science



The Cardiovascular Medicine at Kyoto University, aims at elucidating the cause of the cardiovascular disease and therapeutic measures for it and making their assessment by use of both basic and clinical research approach. We strongly hope that young doctors become balanced clinicians who weight not only cardiovascular emergency medicine but also the preventive medical care. We are also training them to be able to send information about our researches to the world. We have resolved to make significant contributions to the tomorrow’s cardiovascular medicine in Japan.

Takeshi KimuraProfessor

Research and Education■Basic Research·We conduct highly original research in the cardiovascular field using novel strategies of molecular biology, physiology and molecular genetics. Both of the clinical and the basic research are essential for the progress of the cardiovascular medicine. Therefore, our basic research group keeps in close contact with clinical research. ·We try to expand the possibilities of ourselves. Participation of young researchers or those from different fields provide us more extensive studies. We welcome new colleagues who are interested in our research field. ·Our aim is to elucidate the pathophysiology of cardiovascular diseases and develop novel methods of diagnosis and therapeutic strategies. In addition, we perform translational research with wide clinical application.■Clinical ResearchMembers of the Department of Cardiovascular Medicine at Kyoto University are continuously contributing to evidence-based health care through clinical researches and education in the fields of cardiovascular medicine. Currently, we conduct over ten clinical studies including five multicenter randomized controlled trials in collaboration with major foremost hospitals in Japan. The major targets of our clinical research include ischemic heart disease, heart failure, arrhythmia, peripheral artery disease, aortic disease, hypertension, and cardiac rehabilitation.

In detail, please visit our department’s homepage. URL: http://kyoto-u-cardio.jp/

Recent Publications1. Ohno M, Hiraoka Y, Matsuoka T, Tomimoto H, Takao K, Miyakawa T, Oshima N, Kiyonari H,

Kimura T, Kita T, Nishi E. Nardilysin regulates axonal maturation and myelination in the central and peripheral nervous system. Nat Neurosci. 2009 Dec;12(12):1506-13.

2. Horiguchi M, Inoue T, Ohbayashi T, Hirai M, Noda K, Marmorstein LY, Yabe D, Takagi K, Akama TO, Kita T, Kimura T, Nakamura T. Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase. Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19029-34.

3. Inuzuka Y, Okuda J, Kawashima T, Kato T, Niizuma S, Tamaki Y, Iwanaga Y, Yoshida Y, Kosugi R, Watanabe-Maeda K, Machida Y, Tsuji S, Aburatani H, Izumi T, Kita T, Shioi T. Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice.Circulation. 2009 Oct 27;120(17):1695-703.

4. Kimura T, Morimoto T, Nakagawa Y, Tamura T, Kadota K, Yasumoto H, Nishikawa H, Hiasa Y, Muramatsu T, Meguro T, Inoue N, Honda H, Hayashi Y, Miyazaki S, Oshima S, Honda T, Shiode N, Namura M, Sone T, Nobuyoshi M, Kita T, Mitsudo K; j-Cypher Registry Investigators. Antiplatelet therapy and stent thrombosis after sirolimus-eluting stent implantation. Circulation. 2009 Feb 24;119(7):987-95. Epub 2009 Feb 9.

5. Kimura T, Morimoto T, Furukawa Y, Nakagawa Y, Shizuta S, Ehara N, Taniguchi R, Doi T, Nishiyama K, Ozasa N, Saito N, Hoshino K, Mitsuoka H, Abe M, Toma M, Tamura T, Haruna Y, Imai Y, Teramukai S, Fukushima M, Kita T.Long-term outcomes of coronary-artery bypass graft surgery versus percutaneous coronary intervention for multivessel coronary artery disease in the bare-metal stent era. Circulation. 2008 Sep 30;118(14 Suppl):S199-209.

6. Nishiyama K, Horiguchi M, Shizuta S, Doi T, Ehara N, Tanuguchi R, Haruna Y, Nakagawa Y, Furukawa Y, Fukushima M, Kita T, Kimura T. Temporal pattern of strokes after on-pump and off-pump coronary artery bypass graft surgery.Ann Thorac Surg. 2009 Jun;87(6):1839-44.

7. Ozasa N, Furukawa Y, Morimoto T, Tadamura E, Kita T, Kimura T. Relation among Left Ventricular Mass, Insulin Resistance, and Hemodynamic Parameters in Type 2 Diabetes. Hypertension Research 2008; 31: 425-432.

❶ A Murine Model of Acute Myocardial Infarction

❷ Hypertensive Heart Failure in Dahl Salt-Sensitive Rat

❸ Cardiac Catheterization Laboratory ❹ Biostatics Seminar for Graduate

Students and young doctors ❺ Staff of Department of Cardiovascular

Medicine

Cardiovascular MedicineProfessor : Takeshi Kimura Associate Professor : (Industry-Academia Collaboration) Eiichiro Nishi Senior Lecturer : Noriaki Kume, Tetuo Shioi, Koh Ono (Hakubi Project) Associate Professor : Motoko Yanagida Assistant Professor : Yoshiki Yui, Chiharu Kishimoto, Satoshi Shizuta, Neiko Ozasa, Takeru Makiyama (Industry-Academia Collaboration) Yoshinori Hiraoka, Mikiko Ohno, Masao Imai TEL : +81-75-751-3185 FAX : +81-75-751-3289 e-mail : [email protected] URL : http://kyoto-u-cardio.jp/

Cardiovascular Medicine

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Our department has been established in 1996 as the first Department of Gastroenterology and Hepatology in all the national university in Japan. At that time, because our staff members and graduate students got together from various places in and outside of Kyoto university, the present members consist of a wide variety of people, whose carrier and medical school vary. As a clinical department, our goal is to produce many good clinical specialists for gastroenterology, who can understand both clinical medicine and basic science, and to create new modalities for treatment of various gastroenterological diseases.

Tsutomu Chiba, M.D., Ph.D.Professor

Research and EducationPeriods of internship and residency are very important for young doctors to become good physicians. So, we are doing our best to educate young doctors to become general internists as well as good gastroenterologists. In particular, after finishing internship and residency, we prepare a special course for training clinical gastroenterology together with many affiliated hospitals. Similar to clinical works, our research projects cover liver diseases, pancreatico-biliary diseases, and upper and lower gastrointestinal tract diseases. Particularly, we are focusing on cancers, immunological diseases such as inflammatory bowel disease, and regeneration of gastrointestinal organs. Now, in order to enhance our ability of accomplishing research, we are sending young fellows to several distinguished research laboratories of basic medical science. In addition, there are quite a few young investigators, who are now doing research work in abroad. For these 13 years after establishment, we have clarified significance of occult infection of HBV in the development of liver cancer, roles of immunological responses to H. pylori in the development of various gastric diseases such as gastric cancer and MALT lymphoma, and have developed a novel method for treatment of IBD. Moreover, we made significant contribution to establishing the concept of autoimmune pancreatitis, and methods for treating post-operative biliary stricture after living-related liver transplantation. From now, we are going to establish treatment methods for various gastrointestinal cancers and IBD, and to develop method for regeneration of liver, that can substitute liver transplantation.

Recent Publications1. Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, Azuma T, Okazaki IM,

Honjo T, Chiba T: Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 13:470-476:2007.

2. Ikeda K, Marusawa H, Osaki Y, Nakamura T, Kitajima N, Yamashita Y, Kudo M, Sato T, Chiba T: Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carcinoma: a prospective study. Ann Intern Med 146:649-656:2007.

3. Kido M, Watanabe N, Okazaki T, Akamatsu T, Saga K, Nishio A, Tanaka J, Honjo T, Chiba T : Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling. Gastroenterology 135:1333-1343:2008.

4. Takai A, Toyoshima T, Uemura M, Kitawaki Y, Marusawa H, Hiai H, Yamada S, Okazaki IM, Honjo T, Chiba T, Kinoshita K : A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations. Oncogene 28:469-478:2009.

5. Matsumoto Y, Marusawa H, Kinoshita K, Niwa Y, Sakai Y, Chiba T : Up-regulation of activation-induced cytidine deaminase causes genetic aberrations at the CDKN2b-CDKN2a in gastric cancer. Gastroenterology 139:1984-1994:2010

❶ Histology of the gastric mucosa of H. pylori-infected neonatally thymectomized mice.

Massive infiltration of lymphocytes forming lymphoid follicles in the body mucosa at 12 months after H. pylori infection in neonatally thymectomized mice, which resembles histology of human MALT lymphoma.

❷ While early detection of squamous cell carcinomas in the head and neck region and the esophagus have been quite difficult by conventional white light image (A), NBI can effectively detect them.

❸ staffs

Gastroenterology and HepatologyProfessor : Tsutomu Chiba Associate Professor : Manabu Muto, Norihiko Watanabe, Tomohiro Watanabe Senior Lecturer : Hiroshi Nakase, Naoshi Nishida, Hiroshi Seno, Hiroyuki Marusawa, Yoshihide Ueda Assistant Professor : Shinichi Miyamoto, Yasumasa Ezoe, Takahiro Horimatsu, Hiroshi Ida, Hideyuki Komekado, Shuko Morita, Yuzo Kodama, Yuko Matsumoto, Minoru Matsuura TEL : +81-75-751-4319 FAX : +81-75-751-4303 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~gastro/

gastro.html

Gastroenterology and Hepatology

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Respiratory diseases have marked variability such as obstructive airway diseases, interstitial lung diseases, lung cancer, respiratory infection, sleep disorders and respiratory insufficiency. We are energetically engaged in the study of all these diseases. In the 21st century, the concept “physiome”, which means that the integration of the achievement of molecular-cell biology form the view point of organ biology, will be more important. We hope we can create a new world of respiratory medicine based on “physiome”.

Michiaki Mishima, M.D., Ph.D.Professor

Research and EducationOur clinical, educational and research activities are performed on five categories; obstructive pulmonary disease, interstitial pulmonary disease, lung cancer, respiratory infection and sleep disorders / pulmonary insufficiency.

(1) Obstructive pulmonary disease (bronchial asthma, COPD)We study how to control the refractory asthma and cough variant asthma, and investigate the etiology of COPD. The type of inflammation of airway in smokers, disease susceptibility of COPD and the mechanism of airway remodeling in refractory asthma are also studied.

(2) Interstitial pneumonia (sarcoidosis, idiopathic interstitial pneumonia and collagen disease related lung)The mechanism of the variability of pulmonary fibrosis, lymphocyte proliferation and regulation of T cell in the process of fibrosis are investigated.

(3) Lung cancerThe recent prolongation of the life span in patients with the advanced lung cancer is indebted to the anticancer drugs of the third generation, and we are now performing multi-center clinical trial to find the best combination of the drugs. The metastatic factor of the lung cancer and the side effects of the molecular targeted drugs are also investigated.

(4) Respiratory infectionGenomic analysis and development of vaccines of TB and atypical mycobacterium and another bacteria are investigated. The immune system of the host is also studied.

(5) Sleep disorders / pulmonary fibrosisThe optimized protocol of non-invasive positive pressure ventilation (NIPPV) is investigated toward the patients with pulmonary insufficiency and sleep disorders such as obstructive sleep apnea. The effect of NIPPV on the life span is also studied based on adhesion molecule and inflammatory cytokine.

Recent Publications1. Terada K, Muro S, Sato S, et al. Impact of gastro-oesophageal reflux disease symptoms on COPD

exacerbation. Thorax 2008;63:951-5 2. Ueda T, Niimi A, Matsumoto H, Takemura M, et al. TGFB1 promoter polymorphism C-509T and

pathophysiology of asthma. J Allergy Clin Immunol 2008;121:659-64. 3. Masago K, Fujita S, Kim YH,et al. Effect of vascular endothelial growth factor polymorphisms on

survival in advanced-stage non-small-cell lung cancer. Cancer Sci. 2009;100:1917-22. 4. Handa T, Nagai S, Kitaichi M, et al. Long-term complications and prognosis of chronic beryllium

disease. Sarcoidosis Vasc Diffuse Lung Dis 2009;26:24-31. 5. Osawa M, Ito Y, Hirai T, et al. Risk factors for invasive aspergillosis in living donor liver transplant

recipients. Liver Transpl. 2007;13:566-70.

❶ Original CT image and colored image of pulmonary emphysema, where each emphysema cluster was described in the different colors.:

Fractal analysis using size and number of emphysema clusters offers useful information about the detection of early emphysema.

❷ Comparison of the airway wall between the different stage of bronchial asthma : The airway wall thickened as the stage of asthma progressed. CT images can detect the

permanent change of airway wall construction (airway remodeling) in vivo.

Respiratory MedicineProfessor : Michiaki Mishima Associate Professor : Akio Niimi Senior Lecturer : Toyohiro Hirai Assistant Professor : Shigeo Muro, Hisako Matsumoto, Yutaka Ito, Kim Younghhak, Yuma Hoshino, Isao Ito, Katsuhiro Masago, Tsuyoshi Oguma, Daisuke Kinose TEL : +81-75-751-3830 FAX : +81-75-751-4643 e-mail : [email protected] URL : http://www.kukonai.com/

Respiratory Medicine

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The Department of Rheumatology and Clinical Immunology is dealing with researches, education and clinical survice of diseases in which immunological abnormalities are involved in development and pathogenesis, including autoimmune diseases, connective tissue diseases, rheumatic diseases and allergic diseases. Besides, since the therapeutic application of immunology covers infection, transplantation and cancer therapy, clinical Immunology will become more important field in terms of its wide application. We aim to establish the base of clinical immunology and rheumatology in Japan, by elucidating the mechanisms of autoimmune diseases, developing the new diagnostic and therapeutic strategy, offering the advanced clinical service, and training the leading researchers and specialists in this field.

Tsuneyo Mimori, M.D., Ph.D.Professor

Research and EducationWe are now conducting the following studies to examine etiology and pathogenesis of systemic autoimmune diseases and to develop new diagnostic and therapeutic strategy for these diseases.

1) Clinical and pathogenic significance of autoantibodies in connective tissue diseases: We discovered many autoantibodies in connective tissue/ rheumatic diseases, identified their target autoantigens, and elucidated their clinical and pathogenic significance. We are now developing the assay systems to detect those autoantibodies (Fig.1).

2) Cloning of novel target antigens for autoantibodies in rheumatoid arthritis and analysis of their function: Target autoantigens (calpastatin and follistatin-related protein (FRP)) recognized by novel autoantibodies in rheumatoid arthritis (RA) showed inhibitory effects of inflammation. We have demonstrated that FRP and calpain inhibitor ameliorated experimental arthritis in mice (Fig.2).

3) Mechanism of autoantibody production and regulation of autoimmune diseases in lupus model mice: We aim the immunosuppressive treatments specific for autoantibody synthesis or autoreactive (pathogenic) Th cell activation. To develop the new strategy of disease-associated Th clone-specific immunoregulatory treatments in SLE, we demonstrated the therapeutic effects of Th cell vaccination on murine lupus nephritis (Fig.3).

4) Chemokine, cell adhesion molecule and signal transduction in cell activation: Fractalkine is the unique chemokine with chemo-attractive and adhesive functions, and expressed on inflammatory cytokine-activated endothelial cells. We are investigating the role of fractalkine in vascular damage. To clarify the pathogenesis of autoimmune diseases, we are also investigating the function of lipid rafts in apoptosis and activating signal pathways.

5) Analysis of differentiation mechanism in helper T cells and gene therapy by immunosuppressive molecules: We have analyzed the molecular mechanism of helper T cell differentiation into Th1 and Th2 cells and established a new model of it including cross-talks among IL-12, Stat4, T-bet and GATA-3 (Fig.4). Now, we are focusing on the development of an organ- and/or disease-specific new-generation gene therapy to autoimmune diseases using antigen-specific CD4 T cells and/or specific-epitope expressing dendritic cells that are introduced immune-regulatory molecules by virus vectors.

Recent Publications1. Kawabata D, Tanaka M, Fujii T, Umehara H, Fujita Y, Yoshifuji H, Mimori T, Ozaki S:

Ameliorative effects of follistatin-related protein/TSC-36/FSTL1 on joint inflammation in a mouse model of arthritis. Arthritis Rheum 50(2):660-668, 2004

2. Tanaka M, Ozaki S, Kawabata D, Kishimura M, Osakada F, Okubo M, Murakami M, Nakao K, Mimori T: Potential preventive effects of follistatin-related protein/TSC-36 on joint destruction and antagonistic modulation of its autoantibodies in rheumatoid arthritis. International Immunology 15(1):71-77, 2003

3. Yoneda O, Imai T, Nishimura M, Miyaji M, Mimori T, Okazaki T, Domae N, Fujimoto H, Minami Y, Kono T, Bloom ET, Umehara H: Membrane-bound form of fractalkine induces IFN-gamma production by NK cells. Eur J Immunol 33(1):53-58, 2003.

4. Fujii T, Okada M, Mimori T, Craft J: The transmembrane form of TNF-alpha drives autoantibody production in the absence of CD154: studies using MRL/Mp-Fas(lpr) mice. Clin Exp Immunol 130(2):224-232, 2002

❶ Detection of autoantibodies in patients with connective t i ssue d i seases by RNA-immunoprecipitation assay

❷ Amel io ra t i ve e f fec t o f FP (follistatin-related protein) in collagen-mouse arthritis

❸ Ameliorative effect of irradiated DNA-specific autoreactive T cell clone against lupus nephritis in MRL-lpr mouse

❹ Mechanisms of differentiation in helper T cells

Rheumatology and Clinical ImmunologyProfessor : Tsuneyo Mimori Associate Professor : Takao Fujii, Takashi Usui Assistant Professor : Koichiro Ohmura, Takaki Nojima, Daisuke Kawabata, Naoichiro Yukawa TEL : +81-75-751-4380 FAX : +81-75-751-4338 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~rheum/

Rheumatology and Clinical Immunology

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The Department of Geriatric Medicine, which was founded in 1968, is one of the oldest medical departments with specific commitment for the medical science and clinical service for the elderly patients in Japan. With the population rapidly ageing at unprecedented pace, the spectrum of diseases we tackle has been shifted accordingly; patients with cognitive disorders are increasing in number along with such diseases as cerebrovascular and cardiac disorders, malignant neoplasm and infections. Considering the comorbidity and chronic course of the diseases of elderly patients and to sustain their physical functions properly at home, we have implemented several measures including team-based medical care with the support provided by non-medical as well as medical multidisciplinary professionals. As mentioned below, we also devote ourselves to scientific research activities such as studies on pathogenesis, prevention and treatment of various diseases common to elderly patients and studies on cellular senescence.

Research and EducationSince its establishment of the department, our research activities have focused on historically studies on organ-based medicine such as diabetology, neurology, gastroenterology, lipidology and cardiology. Along with these, our current research activities encompass new approaches in geriatric medicine, cognitive neurology and a study on cellular senescence. As to the studies on neurological disorders of elderly people, we are developing a method using neuropsychological and imaging technique to diagnose Alzheimer disease at an early stage. We also study factors related to the progression of dementia. It is also our important research target to develop new approach to relieve caregiver burden and to improve quality of life of dementia patients. As to the comprehensive geriatric assessment, we are assessing the ADLs, physical and mental functions of elderly patients with multidisciplinary professionals to see which factors are affecting on quality of life of them. To develop a novel preventive medical approach, we have established anti-ageing clinic since 2006. The purpose of the clinic is prevention and reduction of bed-bound state, based on up-date information on general ageing. For example, we treat post-menopause women for dislipidemia and osteoporosis, while we treat elder people as general clinician. Our educational program includes learning of history and frontier question in ageing research, which could be applicable to the future clinical approach. In our clinical trial, serum oxidative stress is under examination among patients. We also scope stress-induced senescence as basic research. Our keen interest is to disclose the protective effect of enhanced glycolysis during ageing process. Lastly, with a sure prediction of an increase of elder population in global level, we continue to educate young researchers in the field of gerontology in both clinical and basic and to train clinical fellows in geriatric medicine. Recent Publications

1. Takechi H, et al. (2010) Scenery Picture Memory Test, a New Type of Quick and Effective Screening Test to Detect Early Stage Alzheimer Disease Patients. Geriat Gerontol Int 10; 183-190.

2. Artero-Castro A, et al.(2009) Cold-inducible RNA-binding protein bypasses replicative senescence in primary cells through extracellular signal-regulated kinase 1 and 2 activation. Mol Cell Biol. 29, 1855-68.

3. Dodge H, et al. (2008) Healthy cognitive aging and leisure activities among the oldest old in Japan: Takashima study. J Gerontol A Biol Sci Med Sci. 63:1193-200.

4. Kondoh H. (2008) Cellular life span and the Warburg effect. Exp Cell Res. 314, 1923-8. 5. Kondoh,H. et al.(2005) Glycolytic enzymes can modulate cellular life span. Cancer Research

65,177-185. 6. Nomura, I,et al, (2005) Inhibition of long term potentiation by amyloid beta is mediated in a

mechanism independent of NMDA receptor or VDCC in hippocampal CA1 pyramidal neurons. Neurosci. Lett 391,1-6

❶ A snap shot of meeting with rehab staffs on the progress of our patients

❷ Concept of anti-aging clinic in our department

❸ PET imaging of Alzheimer amyloid

❹ Young and aged cells

Geriatric MedicineSenior Lecturer : Hajime Takechi Assistant Professor : Hiroshi Kondoh, Yoshiyuki Hamakawa TEL : +81-75-751-3460 FAX : +81-75-771-9784 e-mail : [email protected] URL : http://www.geriatric.kuhp.kyoto-u.ac.jp/

Geriatric Medicine

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The department of Diabetes and Clinical Nutrition was founded as the Nutritional Care Unit of Kyoto University Hospital in 1933, and became the division of Clinical Nutrition in 1981 as a central clinical facility. In 1992, the department was reestablished to reflect its academic and scientific roles of providing advanced instruction to medical students in the roles of metabolism and nutrition as well as research opportunities for graduates students in diabetology and nutritional research. We are very active in research and publication, and we encourage ambitious students to consider joining us.

Nobuya Inagaki, M.D., Ph.D.Professor

Research and EducationOur major interest is to clarify the mechanisms of the onset of metabolic disease, especially diabetes mellitus. Our studies include the production and secretion of insulin in pancreatic Beta-cells (Fig.1), secretion and action of the incretins such as GIP and GLP-1 (Fig.2), development of Beta-cell imaging, pathophysiological and genetic studies of diabetes mellitus, metabolism in Beta-cell and liver, transplantation of pancreatic Beta-cells, clinical study of diabetic mellitus and nutritional disorders, and development of stimulation system of energy metabolism. For example, we recently have shown that gastrointestinal polypeptide secreted in the duodenum plays a critical role in the maintenance of glycemic homeostasis and succeeded in islet transplantation from a living donor .Each research project is independent, and all graduate students are allowed freedom to pursue their interest. The teaching staff contributes timely encouragement, discussion, and advice, and teaches the practical techniques required to carry out the experiments. We investigate physiology, pathology, and molecular and cellular biology using animal models and the most advanced analytical methods. During the course of the research, the student learns the numerous skills required for systematic analysis and scientific decision making.

Recent Publications1. Inagaki N. et al. Reconstitution of IATP: an inward rectifier subunit plus the sulfonylurea receptor.

Science. 1995: 270(5239):1166-70 2. Yamada K, Inagaki N. et al. A real-time method of imaging glucose uptake in single, living

mammalian cells. Nat. Protoc. 2007: 2(3)753-62 3. Fujita Y, Inagaki N. Metformin suppresses hepatic gluconeogenesis and lowers fasting blood

glucose levels through reactive nitrogen species in mice. Diabetologia. 2010 Jul;53(7):1472-81. 4. Yoshihara E, Inagaki N, et al. Disruption of TBP-2 ameliorates insulin sensitivity and secretion

without affecting obesity. Nat Commun. 2010 Nov;1(8):127. 5. Mukai E, Inagaki N. et al. Exendin-4 suppresses SRC activation and reactive oxygen species

production in diabetic Goto-Kakizaki rat islets in an Epac-dependent manner. Diabetes. 2011: 60(1):218-26.

6. Nishi Y, Inagaki N. Role of Mitochondrial Phosphate Carrier in Metabolism-Secretion Coupling in Rat Insulinoma Cell Line INS-1. Biochem J. 2011 in press.

❶ The mechanism of insulin secretion.The figure indicates the mechanism of insulin secretion from pancreatic beta cells by the stimulation of glucose or hypoglycemic agents. Several agents use in the treatment of diabetic patients are the target of our research.

❷ The roles of incretin in glycemic homeostasis.Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the physiological incretin that stimulates insulin release upon ingestion of nutrients. To clarify the roles of these hormones in the maintenance of glycemic homeostasis, we are carrying out various experiments using various gene targeting mice.

❸ The research meeting.Graduate students make a presentation about their experimental data in English.

❹ The clinical conference is held once a week.We discuss about the problems in each patient.

❺ The scene on experiment. Each graduate student has some independent research projects and teaching-stuffs advise timely.

Diabetes and Clinical NutritionProfessor : Nobuya Inagaki Associate Professor : Shimpei Fujimoto Senior Lecturer : Kazuaki Nagashima Senior Lecturer (Special Appointment) : Shin-ichi Harashima Assistant Professor : Kentaro Toyoda, Akihiro Hamasaki, Yoshihito Fujita, Norio Harada Assistant Professor (Special Appointment) : Yasuhiko Nakamura, Masahito Ogura, Shunsuke Yamane, Yukari Takeda

Diabetes and Clinical Nutrition

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Our department, responsible for the fields of primary care and emergency medicine, was established in April 2006. Our initial focus and the expectations of people around us were to enhance the quality of emergency medical care and to improve the education of medical students, residents, and other medical providers. The staff members gathered to achieve these goals come from different medical schools and have been trained in various specialties. Our department has a positive attitude and a very free atmosphere. In the future, we would like to contribute to the design of regional medical systems for emergencies and natural disasters and the education of related health care professionals, while preparing to receive, educate, and train graduate students. We hope that many people will be interested in working with us at Kyoto University to develop this new field.

Kaoru Koike, MD, PhD.ChairmanProfessor

Research and EducationEmergency medicine is the starting point of medical science. We aim to provide high-quality medical care at any time, 24 hours a day, 365 days per year. Clinically, we are working hard every day, mainly treating patients who require emergency services. Our daily motto is “for the patient.” Emergency medical care requires a multidisciplinary approach, going beyond the borders of traditional specialties. We thus have a central role in managing and coordinating the services provided by the departments in our university hospital and thereby promptly provide optimal medical care and services to critically ill patients. We are planning to have our own beds in the future. 【Research and education】In 2008, we plan to start basic research on conditions such as serious trauma, sepsis, and burn injuries. Current research topics include “the development of educational techniques for emergency medicine and primary care,” “the development of methods for the dissemination of community-based cardiopulmonary resuscitation,” “the design of medical systems for major disasters,” “the design of in-hospital emergency systems,” “improved emergency medical care before hospital admission,” and “the design of regional networks for emergency medical care.” These topics cover diverse fields, ranging from the response of hospitals to special circumstances to the establishment of community-based networks and the education of health care professionals and the general public. Our department plays a leading role in the development of systems for cardiopulmonary resuscitation and disaster medicine in Japan. Although our department was established only a short time ago, we are now making many presentations at both international and domestic congresses and serve as members of the organizational and steering committees of medical societies involved in emergency medicine. As for education, we are currently focusing on ways to improve education and training during the first few years after graduation from medical school. Major advances have been made in different specialties, and organ-specific diagnosis and treatment has received increasing attention. Because we are usually the first department to come in contact with critically ill patients, our educational and training programs emphasize the basic processes of diagnosis and treatment, i.e., potential diagnoses are made on the basis of patients’ medical history and physical findings; appropriate examinations are then performed to narrow the diagnosis. To effectively treat patients in whom emergency procedures are indicated by their main symptoms and vital signs, our training programs stress the importance of developing the ability to perform diagnosis and treatment in parallel. We have actively introduced off-the-job training, which has recently assumed increasing importance, and are now developing new training techniques to further enhance clinical education. We are planning to also participate in the education of medical students, as well as the development of training-based medical education programs.

Recent Publications1. Nishiyama K, et. al. Chronic obstructive pulmonary disease-An independent risk factor for long-

term cardiac and cardiovascular mortality in patients with ischemic heart disease. Int J Cardiol 2010 Aug 20;143(2):178-83.

2. Nishiyama K, et al. Temporal pattern of strokes after on-pump and off-pump coronary artery bypass graft surgery. Ann Thorac Surg. 87:1839-44, 2009.

3. Hirakawa K, Koike K, et al. Experimental estimation of postmortem interval using multivariate analysis of proton NMR metabolomic data. Legal Medicine 11: S282-S285,2009

4. Suzuki T, et al. Mitogen activated protein kinase mediates non-genomic pathway of estrogen on T cell cytokine production following trauma-hemorrhage. Cytokine. 2008;42:32-8.

5. Suzuki T, et al. Estrogen-mediated activation of non-genomic pathway improves macrophages cytokine production following trauma-hemorrhage. J Cell Physiol. 2008;214:662-72.

Primary Care & Emergency MedicineProfessor : Kaoru Koike,M.D.,Ph.D. Senior Lecturer : Kakuo Sato, MD. Kei Nishiyama, MD. Takao Suzuki, MD. Assistant Professor : Shigeru Ohtsuru, MD. Genta Kato, MD. Ryosuke Nishio, MD. TEL : +81-75-751-4210 FAX : +81-75-751-4211 e-mail : [email protected] URL : http://kuhp.kyoto-u.ac.jp/~qqigaku/

Primary Care & Emergency Medicine



The mission of scientists in the Section of Nephrology is to provide the highest level of patient care, and to conduct basic laboratory and clinical research. Using the latest techniques in biomedical science, molecular biology, immunology, cell biology, knockout mice and iPS cells, researchers investigate the pathophysiology of kidney disease; function of key molecules; effects of many medicine; the cause and treatment of interstitial fibrosis; regeneration of kidney; and the development of new and improved methods to diagnose glomerulosclerosis.

Research and EducationBasic research is now mainly focused on tubulo-inters t i t ia l in jury, d iabet ic nephropathy, and regeneration of kidney.

i) Novel strategy for the treatment of advanced renal injuries:Tubular damage is a final common pathway leading to end-stage renal disease. Although the administration of bone morphogenetic protein-7 (BMP-7) has been shown to repair established tubular injuries its pathophysiological role remains elusive. We have recently shown that uterine sensitization-associated gene-1 (USAG-1), novel BMP antagonist abundantly expressed in the kidney, is the central negative regulator of BMP function in the kidney. Inhibition of USAG-1 will be promising means of development of novel treatment for kidney diseases.

ii) Mechanism of the development of diabetic glomerulosclerosis (collaborative research with University of Tokushima): Diabetic nephropathy is characterized by the accumulation of extra-cellular matrix in glomeruli. To elucidate these mechanisms, we examine the role of Smad1 for the progression of diabetic nephropathy, which is the transcriptional factor we reported to directly regulate the expression of type IV collagen, the main component of extra-cellular matrix in sclerotic glomeruli.

iii) Regeneration of kidney:We also cooperate with the Kidney regeneration group in CiRA (Kenji Osafune’s lab), focusing on the in vitro regeneration of kidney from human iPS cells for transplantation and development of new therapeutic drugs against renal diseases.

In clinical researches, many studies are going on by clinical fellows, such as the beneficial effect of anti-hypertensive drug on renal hemodynamics, the combined effect of cyclosporin and prednisolone for minimal change nephrotic syndrome, the iron metabolism in Japanese hemodialysis patients, and the role of osteocalcin in CKD-MBD patients. Lastly, to provide the highest level of patient care, we continue to educate and train clinical fellows for developing and acquiring expertise as subspecialists in the field of clinical nephrology.

Recent Publications1. Osafune K.(2010) *In vitro* regeneration of kidney from pluripotent stem cells. Exp.Cell Res.

316(16): 2571-7. 2. Mima A, et al (2008) Urinary Smad1 is a novel marker to predict later onset of mesangial matrix

expansion in diabetic nephropathy. Diabetes. 57(6): 1712-22. 3. Tanaka M, et al (2008) Expression of BMP-7 and USAG-1 (a BMP antagonist) in kidney

development and injury. Kidney Int. 73(2): 181-91. 4. Kanamori H, et al (2007) Inhibition of MCP-1/CCR2 pathway ameliorates the development of

diabetic nephropathy. Biochem Biophys Res Commun. 360(4): 772-7. 5. Sumi E, et al (2007) SRY-related HMG box 9 regulates the expression of Col4a2 through

transactivating its enhancer element in mesangial cells. Am J Pathol. 170(6): 1854-64. 6. Nomura K, et al (2007) Roles of coagulation pathway and factor Xa in rat mesangioproliferative

glomerulonephritis. Lab Invest. 87(2): 150-60.

❶ Disease-specific iPS cells derived from skin cells of a patient with autosomal dominant polycystic kidney disease (ADPKD)

NephrologySenior Lecturer : Atsushi Fukatsu Assistant Professor : Noriyuki Iehara AssistantProfessor (Special Apoinntment) : Takeshi Matsubara TEL : +81-75-751-3641 FAX : +81-75-751-3643 e-mail : [email protected]

Nephrology

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Modern dermatology has completely grown out of conservative old dermatology that described only morphology of skin diseases, thus changing to global cutaneous science which deals with both basic biology and clinical medicine. Our department gathers many specialists including immunologists, allergologists, photobiologists, molecular biologists and hair biologists who try to link basic science with clinical dermatology. Especially, immunodermatology and cutaneous regenerative medicine are two important keywords of our research hopefully leading to fruitful results in dermatology frontier in near future.

Yoshiki Miyachi, M.D., Ph.D.Professor

Research and EducationIn immunodermatology, the biological role of cultured human mast cells in allergic inflammation as well as tissue remodeling, and establishment of human mast cells in animal model using xenotransplantation of human hematopoietic stem cells are under investigation, which may provide valuable tools for investigating allergic skin diseases. Other hot topics in this field include researches on molecular mechanism of contact hypersensitivity using prostaglandin knockout mice, immunological investigation of dendritic cells and chemokine, regulatory T cells in autoimmune skin diseases. Neurophyisiological study of itch is another brand new field of our research.In cutaneous regenerative medicine, molecular biological studies of keratinocytes in wound healing, regeneration of melanocytes as well as hair, cell biological studies of adhesion molecules, connective tissue metabolism in aging, and clinical studies of pressure ulcers are our specialties.In any event, all basic researches should be evaluated in view of clinical impact, because we should return research profits to clinical dermatology contributing to the improvement of clinical outcomes of patients with skin diseases. For graduate students, clinical motivation is absolutely required to start basic research in cutaneous life science, which in turn may broaden their capacity and possibility as physician scientists in future. Our policy in both research and education in graduate school should be greatly appreciated by those who want to join us.

Recent Publications1. Tomura M, Honda T, Tanizaki H, Otsuka A, Egawa G, Tokura Y, Waldmann H, Hori S, Cyster JG,

Watanabe T, Miyachi Y, Kanagawa O, Kabashima K. Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice.

J Clin Invest. 2010 Mar 1;120(3)653-6 2. Moniaga CS, Egawa G, Kawasaki H, Hara-Chikuma M, Honda T, Tanizaki H, Nakajima S, Otsuka

A, Matsuoka H, Kubo A, Sakabe JI, Tokura Y, Miyachi Y, Amagai M, Kabashima K. Flaky Tail Mouse Denotes Human Atopic Dermatitis in the Steady State and by Topical Application with Dermatophagoides pteronyssinus Extract.

Am J Pathol. 2010 May;176(5):2385-93 3. Tanizaki H, Egawa G, Inaba K, Honda T, Nakajima S, Moniaga CS, Otsuka A, Ishizaki T,

Tomura M, Watanabe T, Miyachi Y, Narumiya S, Okada T, Kabashima K. Rho-mDia1 pathway is required for adhesion, migration, and T-cell stimulation in dendritic cells. Blood. 2010 Dec 23;116(26):5875-84

4. Hirai M, Kadowaki N, Kitawaki T, Fujita H, Takaori-Kondo A, Fukui R, Miyake K, Maeda T, Kamihira S, Miyachi Y, Uchiyama T. Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis.

Blood. 2011 Jan 13;117(2):500-9 5. Nakahigashi K, Kabashima K, Ikoma A, Verkman AS, Miyachi Y, Hara-Chikuma M. Upregulation

of Aquaporin-3 Is Involved in Keratinocyte Proliferation and Epidermal Hyperplasia. J Invest Dermatol. 2010 Dec 30. [Epub ahead of print]

❶ Nishimura EK, et. al.: Dominant role of the niche in melanocyte stem cell fate determination. Nature, 416: 854-860, 2002

❷ Kabashima K, et. al.: The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J Clin Invest, 109:883-893, 2002

❸ Morita K, et.al.: Molecular architecture of tight junctions of periderm differs from that of the maculae occludentes of epidermis. J Invest Dermatol, 118:1073-1079, 2002

❹ Staffs

DermatologyProfessor : Yoshiki Miyachi Associate Professor : Kenji Kabashima Senior Lecturer : Yumi Matsumura, Miki Tanioka Assistant Professor : Akiko Arakawa, Mayumi Katoh, Keisuke Egawa, Hideki Tanizaki, Eri Muroga, Atsusi Otsuka TEL : +81-75-751-3310 FAX : +81-75-761-3002 e-mail : [email protected]

Dermatology

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- Clinical Medicine (Core Departments) - Cutaneous Life Science


The most important issue at Department of Pediatrics is development. A number of pediatric disorders are derived from the impairments during developmental process and the investigations disclosing the intrinsic defects lead to the exploitation of new diagnosis and treatment for intractable diseases. We would like to apply our outcomes obtained from clinic and laboratory to children with intractable diseases.

Toshio HeikeProfessor

Research and EducationSeveral projects on stem cell research and regenerative medicine are on progress. We are dealing with wide variety of stem cells such as hematopoietic stem cells, bone marrow-derived multipotent stem cells, skeketal or cardiac muscle stem cells, neural stem cells, liver stem cells including somatic stem cells and embryonic stem cells in a mouse, monkey and a human. We are aiming for the clinical application using these cells.We have developed a new immunocompromised mouse, NOD/SCID/gamma c null mouse, which permits the engraftment and reconstitution of transplanted human cells. The development of this mouse enabled in vivo evaluation of human stem cells for the first time, leading to the establishment of reliable and safe regenerative medicine using human stem cells.

Recent Publications1. Morishima T, Watanabe KI, Niwa A, Fujino H, Matsubara H, Adachi S, Suemori H, Nakahata T,

Heike T.: Neutrophil Differentiation From Human-Induced Pluripotent Stem Cells. J Cell Physiol. 2011

2. Kumada T, Yamanaka Y, Kitano A, Shibata M, Awaya T, Kato T, Okawa K, Abe T, Oshima N, Nakahata T, Heike T.: Ttyh1, a Ca(2+)-binding protein localized to the endoplasmic reticulum, is required for early embryonic development. Dev Dyn. 2010

3. Kaichi S, Hasegawa K, Takaya T, Yokoo N, Mima T, Kawamura T, Morimoto T, Ono K, Baba S, Doi H, Yamanaka S, Nakahata T, Heike T. : Cell line-dependent differentiation of induced pluripotent stem cells into cardiomyocytes in mice. Cardiovasc Res. 2010

4. Mizuno Y, Chang H, Umeda K, Niwa A, Iwasa T, Awaya T, Fukuda S, Yamamoto H, Yamanaka S, Nakahata T, Heike T: Generation of skeletal muscle stem/progenitor cells from murine induced pluripotent stem cells. FASEB J 24:2245-2253, 2010.

5. Sakai H, Ito S, Nishikomori R, Takaoka Y, Kawai T, Saito M, Okafuji I, Yasumi T, Heike T, Nakahata T: A case of early-onset sarcoidosis with a six-base deletion in the NOD2 gene. Rheumatology 49 : 194-62009.

❶ ES-derived satellite-like cells can repair damaged muscle in vivo. ❷ Selective and efficient detection of latent mutation of CIAS1 gene in mosaic CINCA

syndrome

PediatricsProfessor : Toshio Heike Associate Professor : Masahiko Kawai, Ryuta Nishikomori Senior Lecturer : Ken-ichiro Watanabe, Assistant Professor : Hiraku Doi, Takahiro Yasumi, Takeo Kato, Yasunari Yamanaka, Fusako Niwa, Shinji Kaichi, Katsutsugu Umeda, Shiro Baba, Tomonari Awaya, Takeshi Hasegawa TEL : +81-75-751-3290 FAX : +81-75-752-2361 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Pediatrics

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- Clinical Medicine (Core Departments) - Developmental Medicine


We are developing innovative treatment approaches to eradicate cancers which now affect majority of folks. As molecular biological approaches, we are focusing on hypoxic cells within tumors. We are investigating the cause of radioresistance of the hypoxic cells and developing methods to overcome the effects of the hypoxia. On the other hand, as physical and engineering approach, we are driving forward to high-precision radiotherapy such as intensity-modulated radiotherapy and stereotactic irradiation, and 4-D radiotherapy. We welcome the participation of physicians, biologists, and experts in physical engineering who are interested in the development of tumor-targeted treatments customized for characteristics of tumors.

Masahiro Hiraoka, M.D., Ph.D.Professor

Research and Education■Biological approachTumor hypoxia, which is caused by the imbalance between oxygen-consumption in and oxygen-supply to a cancer, has been reported to induce radioresistant phenotype of cancer cells. We have been aiming to elucidate biological mechanism behind the hypoxia-mediated cancer radioresistance. Then, based on the obtained information, we are aiming to develop innovative radiation therapy strategies for cancer.1) Imaging of hypoxic regions in solid tumors by using the reporter construct, 5HRE-Luciferase. We first constructed reporter genes, which express luciferase bioluminescence under the control of HIF-1-dependent promoter, 5HRE. Then, we established a strategy to image tumor hypoxia as HIF-1-dependent bioluminescence in real-time. The imaging system has helped us to elucidate molecular mechanism behind cancer radioresistance and to develop innovative 4-dimentional radiation therapy and chemo-radiation therapy.2) Development of imaging probes and anti-cancer drugs for tumor hypoxia. Through the collaboration with various labs belonging to Graduate School of Pharmaceutical Science and Engineering, we have developed imaging probes and anti-cancer drugs to image and target tumor hypoxia, respectively.■Physical and engineering approachWe are implementing basic researches and clinical applications of advanced high-precision radiation therapy such as intensity-modulated radiotherapy (IMRT), stereotactic irradiation, and image-guided radiotherapy as a physical and engineering approach. We are also developing next-generation 4-dimensional radiotherapy system with tracking irradiation ability. Our final goal is to develop methods for so-called tailor-made radiotherapy in which biological imaging and molecular biological approach are integrated into physical and engineering approach. In April 2005, we have established a Division of Medical Physics in our Department consisted of four staffs in order to build up the framework for both researches and clinical works, where 4D dose calculation algorithm and in-house Monte Carlo dose-calculation system is underdevelopment.

Recent Publications1. Nakamura M, Sawada A, Ishihara Y, et al. Dosimetric characterization of a multileaf collimator

for a new four-dimensional image-guided radiotherapy system with a gimbaled x-ray head, MHI-TM2000, Med. Phys. 37, 4684-.4691, 2010

2. Shiinoki T, Shibuya K, Nakamura M, Nakamura A, Matsuo Y, Nakata M, Sawada A, Mizowaki T, Itoh A, Hiraoka M Interfractional reproducibility in pancreatic position based on four-dimensional computed tomography. Int J Radiat Oncol Biol Phys. Oct 2010 (Accepted)

3. Kizaka-Kondoh S, ltasaka S, Zeng L, Tanaka S.Zhao T. Takahashi Y, Shibuya K, Hirota K, Semenza GL, Hiraoka M. Selective killing of hypoxia-inducible factor-1-active cell improves survival in a mouse model of invasive and metastatic pancreatic cancer. Clin Cancer Res, 2009, 15:3433-41.

4. Harada H, Itasaka S, Kizaka-Kondoh S, Shibuya K, Morinibu A, Shinomiya K, Hiraoka M. The Akt/mTOR pathway assures the synthesis of HIF-1alpha protein in a glucose- and reoxygenation-dependent manner in irradiated tumors. J. Biol. Chem. 284:5332-5342. 2009.

5. Takayama K, Mizowaki T, Kokubo M, Kawada N, Nakayama H, Narita Y, Nagano K, Kamino Y, Hiraoka M. Initial validations for pursuing irradiation using a gimbals tracking system. Radiother Oncol. 93:45-9. 2009

❶ Immunohistochemical analysis of a section of solid tumor with fluorescence-labeled antibodies. The green indicates a blood vessel and the red indicates hypoxic tumor cells.

❷ Real time imaging of hypoxic regions in solid tumors via IVIS-SPECTRUM by using cancer cell lines, which specifically express luciferase under hypoxic conditions.

❸ Orthotopic model for lung cancer : Evaluation of new therapeutic strategy via IVIS-SPECTRUM.

❹ An example of Intensity Modulated Radiation Therapy (IMRT) for prostate cancer. Using 5 ports of intensity modulated beam, large dose of radiation can be delivered while sparing radiosensitive organs such as rectum or femoral head.

Radiation Oncology and Image-Applied TherapyProfessor : Masahiro Hiraoka Associate Professor : Michihide Mitsumori, Akira Sawada Senior Lecturer : Takashi Mizowaki, Keiko Shibuya Assistant Professor : Satoshi Itasaka, Michio Yoshimura, Yukinori Matsuo, Masakazu Ogura, Yoshiki Norihisa, Masaru Nrabayashi, Sayaka Sato, Yuuki Miyabe, Mitsuhiro Nakamura TEL : +81-75-751-3417 FAX : +81-75-771-9749 e-mail : [email protected] URL : http://radiotherapy.kuhp.kyoto-u.ac.jp

Radiation Oncology and Image-Applied Therapy

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- Clinical Medicine (Core Departments) - Radiology and Nuclear Medicine


The Department of Diagnostic Imaging and Nuclear Medicine, since its establishment in 1976, has committed to teaching Diagnostic Radiology and Nuclear Medicine, and practice medical services to patients with a variety of diseases on the basis of imaging. Our Radiology Department provides a full-range of diagnostic services utilizing diagnostic imaging modalities such as X-ray CT, MRI, Ultrasonography, as well as Positron Emission Tomography, and cover the whole fields of internal organs. Interventional Radiology that incorporates both diagnosis and treatment is another service which we have been providing. Today, the Department of Nuclear Medicine and Diagnostic Imaging is leading the way by bringing imaging excellence not only into various departments within our hospital but also into the community with the achievement of biomedical imaging.

Kaori Togashi, M.D., Ph.D.Professor

Research and EducationThe major research interests of the departmental staff include: (1) physical and mathematical investigations for development of the effective use of imaging modalities, (2) establishment of a new method of imaging diagnosis and clinical investigation such as pathological analysis, and (3) basic medical research using biomedical and pathological methods to imaging findings.(4)establishment of a new technology of image-assisted minimally-invasive therapy. We focus research activities mainly on clarification of mechanism with a pathophysiological approach, establishment of a new method of imaging diagnosis, and development of state-of-the-art imaging modalities and its clinical applications. The characteristics of our research are its wide variety in the field and modality, as a result, a wide variety of collaboration with departments of basic sciences, engineering, and medical information. Although our main concern is clinical problem oriented researches, we are also concerning with experimental studies such as development of novel contrast enhancement, molecular imaging, or an evaluation of angiogenesis, oxygenation, blood flow in tumors with a use of state-of-the-art imaging technique.

Education:We heartily wish to serve in the field of education not only for residents who will be a radiologist but also for residents that are scheduled to be doctors in other departments. As an option for the residents in SUPER ROTATION, we are preparing for short courses consisting of two months to develop their skill in the imaging diagnosis, because imaging is mandatory in all the medical fields. Of course, we are waiting for young doctors to grow them up as professional radiologists with a program of four years in two institutions to cover all the major field of body and to be familiar with a variety of examination.

Recent Publications1. Kasahara S, Miki Y, Kanagaki M, Yamamoto A, Mori N, Sawada T, Taoka T, Okada T, Togashi K.

Hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with a history of brain irradiation. Radiology. 2011 Jan;258(1):222-8.

2. Miyake KK, Nakamoto Y, Mikami Y, Ishizu K, Saga T, Higashi T, Togashi K. F-18 FDG PET of foreign body granuloma: pathologic correlation with imaging features in 3 cases. Clin Nucl Med. 2010 Nov;35(11):853-7.

3. Fujimoto K, Nakai A, Okada T, Ikeuchi T, Satogami N, Daido S, Yakami M, Togashi K. Effect of hyoscine butylbromide (HBB) on the uterine corpus:quantitative assessment with T2-weighted (T2W) MRI in healthy volunteers. J Magn Reson Imaging. 2010 Aug;32(2):441-5.

4. Shimada K, Isoda H, Hirokawa Y, Arizono S, Shibata T, Togashi K. Comparison of gadolinium-EOB-DTPA-enhanced and diffusion-weighted liver MRI for detection of small hepatic metastases. Eur Radiol. 2010 Nov;20(11):2690-8.

5. Umeoka S, Koyama T, Watanabe G, Saga T, Kataoka M, Togashi K, Hatabu H.Preoperative local staging of esophageal carcinoma using dual-phase contrast-enhanced imaging with multi-detector row computed tomography: value of the arterial phase images. J Comput Assist Tomogr. 2010 May-Jun;34(3):406-12.

6. Yakami M, Ishizu K, Kubo T, Okada T, Togashi K. Development and Evaluation of a Low-Cost and High-Capacity DICOM Image Data Storage System for Research. J Digit Imaging. 2010 Feb 24.

❶ Fusion image of the tumor, intestine and vessels of a case of cecal cancer scheduled for laparoscopic par tial resection of the colon.

❷ Postoperative case of CABG bypass with lt-internal thoarcic artery bypassed to anterior descending branch of lt-coronary artery.

❸ A case of FDG-PET examination for glucose metabolism in the brain

Diagnostic Imaging and Nuclear MedicineProfessor : Kaori Togashi Associate Professor : Toshiya Shibata, Hiroyoshi Isoda Senior Lecturer : Yuji Nakamoto, Tomohisa Okada (Program-Specific Senior Lecturer) Hiroyuki Sekiguchi Assistant Professor : Ryota Fujimoto, Takeshi Kubo, Mitsunori Kanagaki, Akira Yamamoto, Shotaro Kanao, Shigeaki Umeoka (Program-Specific Assistant Professor) Koji Fujimoto, Masahiro Yakami, Aki Kido, Toyomichi Shibata, Masako Kataoka TEL : +81-75-751-3760 FAX : +81-75-771-9709 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~diag_

rad/

Diagnostic Imaging and Nuclear Medicine

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- Clinical Medicine (Core Departments) - Radiology and Nuclear Medicine


Emerging and re-emerging infectious diseases and increasing drug resistance in various pathogenic microorganisms have created a worldwide interest in infectious diseases. A complex failure in the balance between pathogen, host, and environment causes infectious diseases. While it is thus very important to establish a correct diagnosis and to administer appropriate treatment for infectious diseases, it is also very difficult. Our aims are to develop novel diagnostic methodologies and to identify clinical evidence that will lead to more efficient management of infectious diseases. Our mission is to develop young, promising clinicians and investigators who will take an active part internationally in the fields of clinical infectious diseases, infection epidemiology, and clinical microbiology.

Satoshi Ichiyama, M.D., Ph.D.Professor

Research and EducationInfection is caused by a variety of pathogens from a virion to a multicellular parasite, while infected hosts show a range of immunological status from completely healthy to severely immunocompromised.Many modalities such as microscopical examination, culturing, direct detection of antigens or genomes, are now available for the identification of causative pathogens leading to the initiation of optimal treatment. However, the correct cause cannot always be accurately identified, so that there is a growing need for the development and practical application of new technologies. To meet this need, we are cooperating with the clinical laboratory of Kyoto University Hospital and with many industries for the development and practical use of novel diagnostic methods for infectious diseases.Infections in patients who are immunocompromised or have undergone aggressive surgery are likely to be highly complicating and life threatening. Effective prevention and control of nosocomial infections can be expected to result not only in improved outcomes but also in reduced medical costs. We are therefore conducting research into a thorough surveillance of postoperative or post-transplantation infections as well as into the prevention and control of these infections.Unfortunately, the resources for adequate education in and management of infectious diseases in Japan have been insufficient compared with those available in other developed countries. To improve this situation, scientific rationality, rather than unsubstantiated “authoritative” comments, must take priority for better practice with regard to infectious diseases. At Kyoto University Hospital, we have been providing a sophisticated consultation service regarding efficient diagnostic procedures and appropriate management of patients with severe infection, which has resulted in a steady improvement of the prognosis for patients with nosocomial sepsis. In addition, we are educating both medical students and residents in the management of patients with infectious diseases on the basis of up-to-date clinical evidence.We are continuing to pursue the development and application of novel methods for the diagnosis of infectious diseases, the control as well as prevention of nosocomial infection with the aim of putting everyday medical practice regarding infectious diseases on a foundation of scientific rationality.

Recent Publications1. Close cooperation between infectious disease physicians and attending physicians results in

better outcomes for patients with Staphylococcus aureus bacteraemia. Nagao M, Iinuma Y, Saito T, Matsumura Y, Shirano M, Matsushima A, Takakura S, Ito Y, Ichiyama S. Clin Microbiol Infect. 2010;16:1783-8.

2. First outbreak of methicillin-resistant Staphylococcus aureus USA300 harboring the Panton-Valentine leukocidin genes among Japanese health care workers and hospitalized patients.

Nagao M, Iinuma Y, Suzuki M, Matsushima A, Takakura S, Ito Y, Ichiyama S. Am J Infect Control. 2010;38:e37-9.

3. Regional spread of vanA- or vanB-positive Enterococcus gallinarum in hospitals and long-term care facilities in Kyoto prefecture, Japan. Shirano M, Takakura S, Yamamoto M, Matsumura Y, Matsushima A, Nagao M, Fujihara N, Saito T, Ito Y, Iinuma Y, Shimizu T, Fujita N, Ichiyama S. Epidemiol Infect. 2011;139:430-6.

4. High Prevalence of Mutators in Enterobacter cloacae Nosocomial Isolates and Their Association with Antimicrobial Resistance and Repetitive Detection. Matsushima A, Takakura S, Fujihara N, Saito T, Ito Y, Iinuma Y, Ichiyama S. Clin Microbiol Infect. 2009 Dec 23. [Epub ahead of print]

❶ To assess the impact of intervention by infectious diseases physicians in cases with Staphylococcus aureus bacteremia, a retrospective cohort study of patients with SAB, comparing the management and outcome of patients during the initial (dashed line) and the later (solid line) half of the intervention period. The 30-day mortality significantly decreased in the later period (solid line).

❷ Suppression of explosive emergence of VRE in Kyoto Area : Annual surveillance of VRE since 2005, which about a half of all hospitals and about a third of long-term care facilities participated, revealed that emergence and rapid increase of VRE in Kyoto turned to a gradual suppression after the promotion of regional infection control measures with VRE guidelines.

❸ Molecular epidemiology of vanA- or vanB- positive Enterococcus gallinarum detected in Kyoto Area. A major clone of vanA- or vanB- positive Enterococcus gallinarum was found from PFGE analysis. These isolates possessed vanA gene with the same transposon structure of vanA-positive E. faecium which had been detected from multiple hospitals in Kyoto Area. This implicates that regionwide approach would be required to suppress the emergence of VRE capable of spread by horizontal, interspecies gene transfer of resistance gene.

❹ staffs

Clinical Laboratory MedicineProfessor : Satoshi Ichiyama Associate Professor : Shunji Takakura Senior Lecturer : Junko Ito Assistant Professor : Takahiro Doi, Miki Nagao, Aki Matsushima TEL : +81-75-751-3502 FAX : +81-75-751-3233 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/%7Eict/

labmed.html

Clinical Laboratory Medicine

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- Clinical Medicine (Core Departments) - Clinical Bioregulation


Department of Surgery was reorganized into three new divisions in April 2006: Gastrointestinal Surgery, Hepatobiliary-pancreas Surgery & Transplantation, and Breast Surgery. Division of Gastrointestinal Surgery focuses on surgical treatments of gastrointestinal (esophageal, gastric, colorectal) carcinomas, inflammatory bowel diseases and morbid obesity. The division offers comprehensive surgical education to the medical students and young surgeons, and a strong foundation for basic surgical research related to the field to the graduate students. Recent advances in laparoscopic surgery have led us to minimally invasive, yet more refined operation compared with classical open-abdominal surgery. The finest-quality laparoscopic surgeries performed in our division are reflection of the rigorous surgical training and sturdy basic surgical research.

Yoshiharu Sakai, M.D., Ph.DProfessor

Research and EducationMain topics of surgical researches are as follows: 1) molecular biological analysis of gastrointestinal carcinomas to estimate the prognosis or the efficacy of chemoradiotherapy, 2) evaluation of gastrointestinal physiology after surgical procedures, 3) development of new imaging system to unveil and understand more details of surgical anatomy, 4) development of novel surgical procedures and surgical instruments, 5) active involvement in the multi-institutional clinical studies to evaluate outcome of the surgical treatments. Laparoscopy and thoracosopy have provided the clear, magnified view even in the narrowest of the human body space and contributed to disclose the surgical anatomy beyond what was once thought the limitation of the human eyes. The new surgical procedures with less damage on the surrounding organs or tissues would be grounded on the new imaging technique that could detail the surgical anatomy to the levels previously unseen. These new procedures must be further evaluated with the physiological examination and the clinical outcome examination. A rigorous surgical training program and firm basic surgical research are fundamental to obtain the best possible clinical outcome. It is critical for surgical trainees to learn from the video of the exquisite operation and to be guided by a skillful, experienced surgeon. We are confident that our program provides both of these in the finest quality.

Recent Publications1. Kawamura J, Nagayama S, Nomura A, Itami A, Okabe H, Sato S, Watanabe G, Sakai Y. Long-term

outcomes of peripheral arm ports implanted in patients with colorectal cancer. Int J Clin Oncol. 13:349-54, 2008.

2. Hosogi H, Nagayama S, Kawamura J, Koshiba Y, Nomura A, Itami A, Okabe H, Satoh S, Watanabe G, Sakai Y. Molecular insights into Peutz-Jeghers syndrome: two probands with a germline mutation of LKB1. J Gastroenterol. 43:492-7, 2008.

3. Okoshi K, Kubo H, Nagayama S, Tabata C, Kadokawa Y, Hisamori S, Yonenaga Y, Fujimoto A, Mori A, Onodera H, Watanabe G, Sakai Y. All-trans-retinoic acid attenuates radiation-induced intestinal fibrosis in mice. J Surg Res. 150: 53-59, 2008.

4. Hisamori S, Tabata C, Kadokawa Y, Okoshi K, Tabata R, Mori A, Nagayama S, Watanabe G, Kubo H, Sakai Y. All-trans-retinoic acid ameliorates carbon tetrachloride-induced liver fibrosis in mice through modulating cytokine production. Liver Int. 28: 1217-1225, 2008.

❶ Lymphangiogenesis in cancer metastasis ❷ The signaling pathway of anti-cancer effect of INF gamma ❸ The role of chemokines during metastais of colon cancer ❹ The interaction of cancer stem cells and mesenchymal cells ❺ The induction of cancer stem cells by mesenchymal cells

SurgeryDivision of Gastrointestinal SurgeryProfessor : Yoshiharu Sakai Associate Professor : Hiroshi Okabe Senior Lecturer : Suguru Hasegawa Assistant Professor : Junichiro Kawamura, Kazutaka Obama, Kenji Kawada, Eiji Tanaka, Shigeru Tsunoda, Masahiro Yamada TEL : +81-75-751-3650 FAX : +81-75-751-3219 e-mail : [email protected]

Gastrointestinal Surgery

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- Clinical Medicine (Core Departments) - Department of Surgery


In our Division of Hepato-Biliary-Pancreatic Surgery & Transplantation, we are practicing multi-modality treatments consisting of surgical operation, chemotherapy, irradiation and others for patients with hepato-biliary and pancreatic malignancies. Even against difficult-to-treat advanced cancers, we are currently undertaking extension of surgical indication based on the latest outcomes of clinical studies and experienced surgical skills. On the other hand, we are introducing minimally invasive surgery such as laparoscopic surgery for both benign and malignant diseases. Liver transplantation for the treatments of end-stage liver failure and hepatic malignancies is the most significant feature of our division. As a worldwide leader in the field of liver transplantation, we are proud of clinical outcomes of our series. It is our goal to lead surgeons of tomorrow through researches with substantial feedback toward clinical practices and by intensive training of surgical skills. Shinji Uemoto, M.D., Ph.D.

Professor

Research and EducationIn hepato-biliary surgery, the studies concerning development of molecular-targeted therapy against hepatocellular carcinoma, mechanism of chemotherapy-induced liver injury, and molecular mechanism of liver fibrosis are conducted. Concerning the realization of regenerative medicine for liver diseases, we execute experiments for differentiation and cell transplantation of several kinds of stem/progenitor cells, for example, ES cells, iPS cells, hepatic stem cells, and hepatic progenitor cells. Furthermore, we are also going to focus on the identification and characterization of cancer stem cells of liver and pancreatic cancer. To improve clinical outcome of pancreatic cancer, we are actively undertaking the international collaborative study on precursors to pancreatic cancer including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). In our research group of pancreatic regeneration, we have shown that dosage of Ptf1a plays an important role in cell fate determination among pancreatic/ bile duct/ and duodenal lineages during organogenesis. We are presently investigating the mechanisms involved in maintenance of pancreatic duct epithelium, which may lead to a breakthrough in pancreatic carcinogenesis to the treatment of pancreatic cancer as our ultimate goals. We have islet transplantation program both in clinical practice and in basic research, which is mainly focused on islet isolation, preservation and transplantation. In the liver transplantation, we have been executing various basic/clinical researches to solve the crisis of donor shortage: Development of “Chimeric liver” using xenogenic hepatic architecture as “scaffold” with replacement of human hepatocytes; Mesenchymal stem cell transplantation with liver transplantation, anticipating various protective and regenerative effects to small/damaged liver grafts; Development of novel strategy/algorithm for intensive portal venous pressure with an emphasis of liver-resident regulatory T-cells; Development of a novel perfusion preservation of liver grafts, accompanied with new concepts of graft “Post-conditioning”.We support graduate students not only to laboratory research, but also to learn advanced medicine and to study abroad. Conferring the degree, they can play active parts in education, research and clinic.

Recent Publications1. Iwaisako, K., Hatano, E., Taura, K., et al. Loss of Sept4 exacerbates liver fibrosis through the

dysregulation of hepatic stellate cells. J Hepatol 49 (5):768-778, 2008 Narita M., Hatano, E., Ikai, I., et al. A phosphodiesterase III inhibitor protects rat liver from

sinusoidal obstruction syndrome through heme oxygenase-1 induction. Ann Surg, 249 (5):806-13, 2009

2. In vitro hepatic maturation of human embryonic stem cells by using a mesenchymal cell line derived from murine fetal livers.

Ishii T, Yasuchika K, Fukumitsu K, Kawamoto T, Kawamura-Saitoh M, Amagai Y, Ikai I, Uemoto S, Kawase E, Suemori H, Nakatsuji N. Cell Tissue Res. 2010 Mar;339(3):505-12.

3. Fukuda A, Kawaguchi Y, Furuyama K, et al. Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice. Diabetes. 2008;57(9):2421-31. 4. Toyoda K, Okitsu T, Yamane S, Uonaga T, Liu X, Harada N, Uemoto S, Seino Y, Inagaki K.

GLP-1 receptor signaling protects pancreatic beta cells in intraportal islet transplant by inhibiting apoptosis. Biochem Biophys Res Com 2008, 367(4), 793-8.

5. 1. Liver Transpl. 2010 Apr;16(4):538-40. Usefulness of the Kyoto criteria as selection criteria for living donor liver transplantation for

hepatocellular carcinoma. Kaido T, Takada Y, Uemoto S.

❶ JNK inhibitor suppressed rat DEN-induced HCC (Hepatology, 49:1944-53, 2009) ❷ Contribution of mouse embryonic stem cell-derived hepatocytes to regeneration of

damaged-model mouse liver after cell transplantation. (Stem Cells. 2007 Dec;25 (12):3252-60.)

❸ Ptf1a as an important factor in cell fate determination among pancreatic/ bile duct/ and duodenal lineages during organogenesis.

❹ Islet transplantation ❺ Chimeric Liver: Luminescence and Albumin

Hepato- Biliary-Pancreatic Surgery and TransplantationProfessor : Shinji Uemoto Associate Professor : Toshimi Kaido Senior Lecturer : Kyoichi Takaori, Yoshiya Kawaguchi, Etsuro Hatano Assistant Professor : Akira Mori, Masaki Mizumoto, Yasuhiro Ogura, Yasuhiro Iwanaga, Kentaro Yasuchika, Kojiro Taura, Toshihiko Masui, Koichiro Hata, Masayuki Koizumi, Jun Yoshizawa TEL : +81-75-751-3651 FAX : +81-75-751-3106 e-mail : [email protected]

Hepato-pancreato-biliary Surgery and Transplantation

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Among Japanese females, the incidence of breast cancer is the highest amongst all cancers. The incidence and mortality rate of breast cancer are rising every year, and it has been demonstrated that these trends differ between Asia and the West. Furthermore, there is a drastic increase in the importance of breast cancer research in this country. In our research group, studies ranging from molecular biological research to clinical trials are performed with the aim of creating a system for optimization and individualization of treatment by means of profound and overall understanding of characteristics of each patient. Novel tools for local therapy and diagnosis are also being investigated extensively. Furthermore, studies of breast cancer prevention according to an individual’s risk profile are being initiated to create a platform for holistic medicine.

Masakazu Toi M.D. Ph.DProfessor

Research and EducationFor opt imizat ion and indiv idual iza t ion of breast cancer treatment based on the concept of multidisciplinary therapy, studies are being performed to create a system for assessing the relationship between biological characteristics of tumours and host and to develop therapeutic algorithms. The analyses of biomarkers include those for gene amplification, gene polymorphism, gene mutation, protein manifestation and phosphorylation. The development of therapeutic algorithms focuses on integrating informatics using laboratory data, pathological findings and clinical information and outcomes.Current breast cancer studies in our group, such those concerning basic science, translational research and clinical trials, include the following: * Breast cancer stem cell and adipose stem cell study* Biomarker study for optimizing systemic and local therapy* Study of circulating tumour cells, endothelial cells and immune cells * Clinical development and application of bio-optical devices * Development of a novel and less invasive therapy* Study of treatment algorithms for breast cancer patientsWe work enthusiastically not only for breast cancer patients but also for further education of young medical doctors and investigators. We are interested in developing international collaborations. We are seeking exceptional, interactive and creative scientists and physicians to develop novel breast cancer research and new treatment paradigms.

Recent Publications1. Ali AM, Toi M, Ueno T. Anti-angiogenic cancer therapy updates. Curr Mol Med. 9:954-66, 2009. 2. Tsuji W, Inamoto T, Yamashiro H, et al. Adipogenesis induced by human adipose tissue-derived

stem cells. Tissue Eng Part A. 15:83-93, 2009. 3. Toi M, Iwata H, Fujiwara Y, et al. Lapatinib monotherapy in patients with relapsed, advanced, or

metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies. Br J Cancer 101:1676-82, 2009.

4. Toi M. Long-term outcomes of aromatase inhibition for breast cancer. Lancet Oncol 9: 8-9, 2008 5. Ueno T, Elmberger G, Weaver TE, et al. The aspartic protease napsin A suppresses tumor growth

independent of its catalytic activity. Lab Invest. Mar;88(3):256-63. Epub 2008

❶ Human adipose tissue-derived stem cells (left) and adipocytes induced by it (right, oil red O staining)

❷ Mammosphere, containing breast cancer stem like cells ❸ laboratory staff room ❹ laboratory room ❺ Operation ❻ CTC(Circulating Tumor Cell) analysis

Breast SurgeryProfessor : Masakazu Toi Associate Professor : Tomoharu Sugie, (Program-Specific) Kitai Toshiyuki Senior Lecturer : Hiroshi Ishiguro Assistant Professor : Takayuki Ueno, Megumi Takeuchi, (Program-Specific) Wakako Tsuji TEL : +81-75-751-3660 FAX : +81-75-751-3616 e-mail : [email protected] URL : http://www.brca.jp/

Breast Surgery

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The original purpose of anesthesiology was reduction of surgery-induced pain. However, the present goal of anesthesiology is control of excessive biological responses induced by a variety of stresses and protection of patients from stress-induced complications. Clinical activity of this department is divided into anesthesia in the operation theater, pain control for a variety of diseases and critical care medicine. We aim to protect a living body from stresses including surgical stresses, pain, injuries and inflammation for the benefit of patients. Our ultimate goal is elucidation of mechanism for stress responses and development of treatment and care for suppression of excessive stress responses.

Kazuhiko Fukuda, M.D., Ph.D.Professor

Research and EducationThe goal of research in this department is to elucidate mechanisms of responses induced by a variety of stresses and to develop management to control stress responses. Anesthetics and opioids have long been used to suppress stress responses induced by surgical stresses, and are clinically indispensable drugs today. However, the mechanisms of action of these drugs have not been completely understood. We are analyzing actions of anesthetics and opioids from many aspects. To analyze pharmacological actions of opioids at the molecular level, we have cloned cDNAs of opioid receptors, and have analyzed intracellular signal transduction mechanisms activated by opioids. Using genetically engineered mice, we are testing the role of the opioid receptor family in the pharmacological actions of inhaled anesthetics, and have demonstrated the possible involvement of the nociceptin receptor and the kappa-opioid receptor in the analgesic action of nitrous oxide. We have shown that benzodiazepines and local anesthetics potentiate corticotropin releasing factor-induced transcription of the proopiomelanocortin gene. During perioperative period, oxygen supply is often reduced by anemia and changes in the cardio-respiratory system, and organs are exposed to hypoxia, which induces hypoxic responses at the organ, cellular and molecular levels. We have analyzed hypoxia-inducible factor (HIF), which plays important roles in cellular hypoxic responses, and demonstrated that perioperatively used drugs and hypothermia can change cellular hypoxic responses by affecting HIF activity and gene expression controlled by HIF. The clinical research group in this department is attempting to develop comfortable anesthetic care for ambulatory surgery and automatic control of intravenous anesthesia.This department is responsible for instruction and clinical training of anesthesiology and critical care medicine for undergraduate and postgraduate students. Residents are trained to obtain the basic capability of life support and anesthetic care in the operation room. Doctors aiming to be board certified anesthesiologists are trained for anesthetic management of special operations, intensive care for various systemic diseases and control of pain caused by various diseases.

Recent Publications1. Koyama, T., Mayahara, T., Wakamatsu, T., Sora, I. and Fukuda, K.: Deletion of mu-opioid receptor

in mice does not affect the minimum alveolar concentration of volatile anesthetics and nitrous oxide-induced analgesia. Br. J. Anaesth. 103, 744-749 (2009).

2. Tsujikawa, H., Shoda, T., Mizota, T. and Fukuda, K.: Morphine induces DNA damage and P53 activation in CD3+ T cells. Biochim. Biophys. Acta 1790, 791-799 (2009).

3. Tanaka, T., Wakamatsu, T., Daijo, H., Oda, S., Kai, S., Adachi, T., Kizaka-Kondoh, S., Fukuda, K. and Hirota, K.: Persisting mild hypothermia suppresses hypoxia-inducible factor 1a protein synthesis and HIF-1-mediated gene expression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R661-671 (2010).

4. Tanaka, T., Takabuchi, S., Nishi, K., Oda, S., Wakamatsu, T., Daijo, H., Fukuda, K. and Hirota, K.: The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages. J. Anesth. 24, 54-60 (2010).

5. Koyama, T. and Fukuda, K.: Involvement of the k-opioid receptor in nitrous oxide- induced analgesia in mice. J. Anesth. 24, 297-299 (2010).

❶ Predicted structure of the opioid receptors.

C l o n i n g o f t h e c D N A s a n d determination of the amino acid sequences demonstrated that the opioid receptors belong to the seven transmembrane receptor family.

❷ Intracellular signal transduction mechanism mediated by the opioid receptors.

Activation of the opioid receptors induces a var ie ty o f ce l lu la r responses, including inhibition of adenylate cyclase, activation of the inwardly rectifier K+ channel and inhibition of the voltage-dependent Ca2+ channel, via activation of the G-protein. Furthermore, activation of mitogen-activated protein kinases by the opioid receptors leads to changes in gene expression and activation of phospholipase A2.

❸ Ef fects of anesthet ics on the hypoxia-inducible factor (HIF).

Propofol, an intravenous anesthetic, inhibits lipopolysaccharide-induced HIF-1 activation and changes in glucose metabolism in macrophage, by suppressing translation of HIF-1alpha from mRNA.

❹ Clinical anesthesia in the operating theater

S t a f f s o f t h e d e p a r t m e n t o f anesthesia perform anesthetic management and teach residents in the operating theater.

AnesthesiaProfessor : Kazuhiko Fukuda Associate Professor : Toshiyuki Arai Senior Lecturer : Hajime Segawa, Kiichi Hirota, Jiro Kurata Assistant Professor : Masahiro Kakuyama, Hidekatsu Furutani, Hisanari Ishii, Takehiro Shoda, Hiroshi Tsujikawa, Keiji Tanimoto, Taizo Hisano, Tomoharu Tanaka, Toshiyuki Mizota, Masami Sato, Katsunori Yokoyama Assistant Professor (Special Appointment) : Makiko Ikeura, Tomohiro Koyama, Toshie Habara TEL : +81-75-751-3433 FAX : +81-75-752-3259 e-mail : [email protected] URL : http://anesthesia.kuhp.kyoto-u.ac.jp/

Anesthesia

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- Clinical Medicine (Core Departments) - Clinical Sciences for Surgical Stresses


In the clinical field of obstetrics and gynecology, we manage physiological and psychological problems during the entire women’s life toward which all medical doctors should face. In addition, obstetricians and gynecologists manage specialized field of pathophysiology; i.e. pregnancy and disease of female pelvic organs. In our department of gynecology and obstetrics, all postgraduate residents can learn characteristics of female pathophysiology, and can acquire basic knowledge about primary care in obstetric and gynecological emergency. In the research field, obstetrics and gynecology contain various research issues such as perinatology, gynelocogical oncology and reproductive pathophysiology.

Ikuo Konishi, M.D.Professor

Research and EducationOur department covers the field of perinatology, gynecological oncology and reproduction. Clinical and research issues which across these fields are discussed among staffs and research fellows in each field.

■Perinatology: In the clinical department of perinatology, we manage patients with high risk pregnancy, fetal anomalies, and with various medical complications. In the field of perinatology, we are investigating the mechanisms of parturition such as regulation of uterine contraction and cervical ripening by prostaglandins or nitric oxide produced in utero. We are also interested in the regulatory mechanisms of fetal development, concerning about feto-maternal energy metabolism, especially in relation to placenta and adipocyte derived factors including leptin and resistin.

■Gynecological oncology: Clinical principle is to select most suitable treatment strategy for each patient. To achieve this purpose, we discuss the results of image diagnosis and pathological diagnosis with radiologists and pathologists in each case. In addition, we have established bloodless and bladder function-preserved radical hysterectomy, which is standard surgical procedure for invasive cervical cancer. In the research field, leiomyoma and ovarian cancer cell lines established in our department are investigated to clarify the tumorgenesis of uterine smooth muscle tumor and ovarian cancer. In addition, new approach of anti-cancer drug delivery system, analyses of immuno-escaping mechanism of cancer and the development of anti-cancer immunotherapy using dendritic cells are undergone.

■Reproduction:We offer a complete spectrum of infertility treatments including In Vitro Fertilization (IVF) and other Assisted Reproductive Technologies. Laparoscopic surgeries are also performed for the infertile women. In the research field, we are interested in ovulation, implantation and placentation; which are all important processes for the establishment of successful pregnancy. To clarify pathophysiology of these processes, we are now investigating the regulatory mechanisms of folliculogenesis and corpus luteum formation in the ovary, identification of molecules which regulate successful implantation, the mechanisms of controlled invasion of placental extravillous trophoblasts into maternal uterus and the regulatory mechanisms of immune factor in implantation.

Recent Publications1. “Oncogenic property of acrogranin in human uterine leiomyosarcoma: direct evidence of genetic contribution in

in vivo tumorigenesis ” N.Matsumura, M.Mandai, M.Miyanishi, K.Fukuhara, T.Baba, T.Higuchi, M.Kariya, K.Takakura, and S.Fujii Clin Cancer Res. 2006 Mar 1;12(5):1402-11. 2. “Immortalized ovarian surface epithelial cells acquire tumorigenicity by Acrogranin gene overexpression ” M.Miyanishi, M.Mandai, N.Matsumura, K.Yamaguchi, J.Hamanishi, T.Higuchi, K.Takakura and S.Fujii Oncol Rep. 2007 Feb;17(2):329-33. 3. “Immune cell contribute to systemic cross-talk between the embryo and mother during early pregnancy in

cooperation with the endocrine system” H.Fujiwara Reproductive Medicine and Biology, 5:19-29, 2006 4. “Intrauterine administration of autologous peripheral blood mononuclear cells promotes implantation rates in

patients with repeated failure of IVF-embryo transfer” S.Yoshioka, H.Fujiwara, T.Nakayama, K.Kosaka, T.Mori and S.Fujii Human Reproduction,21(12):3290-3294,2006 5. “Eph-ephrin A System Regulates Murine Blastocyst Attachment and Spreading” H.Fujii, K. Tatsumi, K.Kosaka, S.Yoshioka, H.Fujiwara and S.Fujii Developmental Dynamics, 235:3250-3258,2006 6. “ Integrin alpha5 is involved in fibronectin-induced human extravillous trophoblast invasion ” BX Zeng, H.Fujiwara, Y.Sato, Y.Nishioka, S.Yamada, S.Yoshioka, M.Ueda, T.Higuchi and S. Fujii J Reprod Immunol. 2007 Feb;73(1):1-10. Epub 2006 Oct 5. 7. “ Precise anatomy of the vesico-uterine ligament for radical hysterectomy ” S.Fujii, K.Takakura, N.Matsumura, T.Higuchi, S.Yura, M.Mandai and T.Baba Gynecol Oncol. 2007 Jan;104(1):186-91. Epub 2006 Sep 22. 8. “Differences in maternal plasma leptin concentration during human pregnancy, induced labor, after cesarean

section without labor and vaginal deliveries: A review.” M. Nuamah, S. Yura, N. Sagawa, H. Itoh and S. Fujii Nepal Journal of Obstetrics & Gynecology, 1: 13-7, 2006 9. “Increased cyclooxygenase-2 expression is correlated with suppressed antitumor immunity in cervical

adenocarcinomas” Chen TH, Fukuhara K, Mandai M, Matsumura N, Kariya M, Takakura K, Fujii S Int J Gynecol Cancer 16(2):772-779, 2006. 10. “Undernutrition inutero augments systolic blood pressure and Cardiac Remodeling in Adult Mouse Offspring-

Possible Involvement of Local Cardiac Angiotensin System in Developmental Origins of Cardiovascular Disease-Endocrinology”

M.Kawamura, H.Itoh, S.Yura, H.Mogami, S.Isuga, H.Makino, Y.Miyamoto, Y.Yoshimasa, N.Sagawa and S.Fujii Endocrinology. 2007 Mar;148(3):1218-25. 2006.

❶ Leptin produced by placental trophoblast is involved in the regulation of fetal-maternal metabolism. ❷ Transformed human ovarian surface epithelial cells formed tumors in the injected mice. ❸ Laeverin, a novel membrane bound aminopeptidase we have cloned from cDNA library derived from

human chorion laeve, is specifically expressed on extravillous trophoblast in human implantaton site. VT, villous trophoblasts; EVT, extravillous trophoblasts.

Gynecology and ObstetricsProfessor : Ikuo Konishi Associate Professor : Hiroshi Fujiwara Senior Lecturer : Masaki Mandai, Keiji Tatsumi, Kenzo Kosaka Assistant Professor : Yukiyasu Sato, Ayako Suzuki, Noriomi Matsumura, Tsukasa Baba, Kazuyo Kakui, Eiji Kondo, Junzo Hamanishi, Shogo Yamamura, Yumiko Yoshioka TEL : +81-75-751-3269 FAX : +81-75-761-3967 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~obgy/

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- Clinical Medicine (Core Departments) - Surgery for Visceral Organs


Urology comprehends a wide range of medical field. Among them, the main interests of our department are in urologic oncology, and in benign diseases including voiding function, transplantation, reproductive medicine, and pediatric urology.In urologic oncology, in particular, we have a long track record of having introduced innovative therapies such as new anticancer drug treatments for urogenital tumors, new types of operation for urinary diversion, and laparoscopic urologic surgeries, of which we have taken the leadership in Japan.The basic policy of our department is to carry out the advanced medicine based on active propulsion of research and education. We offer, not only the standard medical treatments, but highly advanced medical treatments to the patients by constantly introducing the state-of the-art technology and updated knowledge of the time. Osamu Ogawa, M.D., Ph.D

Professor

Research and EducationAs an important part of the surgical section, we try to bring up top quality urologists with sophisticated surgical techniques, who can analyze complicated pathology of urological diseases properly and manage appropriate treatments for the patients. We believe that this task will be efficiently achieved by performing practice of advanced medicine in an education-oriented environment.We have maintained a largest number of endourological surgery, including laparoscopic surgery, in Japan. Therefore, we believe that we can offer an optimal educational environment to young physicians trained as urologic surgeons and educator. Actually, we run a new education program for specialty training in cooperation with the affiliated hospitals since 2006.On research field, we prioritize the practical science that can contribute to real medical treatments. In our lab, more than 10 postgraduate students are engaged in urologic research, and continue to send the high quality results to prestigious international journals. In our major fields such as urologic oncology, voiding function, transplantation, or reproductive medicine, we encourage collaboration with various basic research sections in our university and the foreign laboratories. In addition, we always have several young urologists engaged in research abroad, who will contribute to maintain the research activity at the top-level of the world.In the research area of urological oncology, we have made substantial contribution in the elucidation of the carcinogenic mechanism by using molecular biological methods and the determination of the hereditary cancer risk using molecular epidemiological approach. Recently, we are also actively working with a more clinically relevant anima model system, patient-derived xenograft model in mice. In the area of benign diseases, we have conducted researches on kidney transplantation as well as the outstanding studies on regeneration of the lower urinary tract. More recently, we are now making innovative achievements in the field of voiding dysfunction, by introducing molecular cellular biological approach in this field. In the area of andrology, we conduct basic researches on the mechanism of male infertility.

Recent Publications1. Shimizu Y, Hamazaki Y, Hattori M, Doi K, Terada N, Kobayashi T, Toda Y, Yamasaki T, Inoue TA,

Kajita Y, Maeno A, Kamba T, Mikami Y, Kamoto T, Yamada T, Kanno T, Yoshikawa K, Ogawa O, Minato N, Nakamura E. Kobayashi T, Inoue T, Shimizu Y, Terada N, Maeno A, Kajita Y, Yamasaki T, Kamba T, Toda Y, Mikami Y, Yamada T, Kamoto T, Ogawa O, Nakamura E. SPA-1 controls the invasion and metastasis of human prostate cancer. Cancer Sci. 2011 (in press)

2. Akamatsu S, Takata R, Ashikawa K, Hosono N, Kamatani N, Fujioka T, Ogawa O, Kubo M, Nakamura Y, Nakagawa H. Hum Mol Genet. A functional variant in NKX3.1 associated with prostate cancer susceptibility down-regulates NKX3.1 expression. 2010, 9:4265-72.

3. Kobayashi T, Inoue T, Shimizu Y, Terada N, Maeno A, Kajita Y, Yamasaki T, Kamba T, Toda Y, Mikami Y, Yamada T, Kamoto T, Ogawa O, Nakamura E. Activation of Rac1 is closely related to androgen-independent cell proliferation of prostate cancer cells both in vitro and in vivo Mol Endcrinol, 2010, 24: 722-34.

4. Terada N, Shimizu Y, Kamba T, Inoue T, Maeno A, Kobayashi T, Nakamura E, Kamoto T, Kanaji T, Maruyama T, Mikami Y, Toda Y, Matsuoka T, Okuno Y, Tsujimoto G, Narumiya S, Ogawa O. Identification of EP4 as a potential target for the treatment of castration-resistant prostate cancer using a novel xenograft model. Cancer Res, 2010, 70: 1606-15.

5. Imamura M, Negoro H, Kanematsu A, Yamamoto S, Kimura Y, Nagane K, Yamasaki T, Kanatani I, Ito N, Tabata Y, Ogawa O. Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle. Am J Physiol Renal Physiol 2009, 297:F46-54. 2009

❶ Laparoscopic urologic surgery ❷ M o u s e b e a r i n g xe n o g ra f t

established from clinical cancer specimen

❸ Molecular cellular approach to the urological diseases as a backbone of the basic research

❹ The members of our department

UrologyProfessor : Osamu Ogawa Associate Professor : Hiroyuki Nishiyama Senior Lecturer : Akihiro Kanematsu, Koji Yoshimura, Tomomi, Kamba Assistant Professor : Kazutoshi Okubo, Takahiro Inoue, Yousuke Shimizu, Yoshiyuki Matsui, Masaaki Imamura TEL : +81-75-751-3325 FAX : +81-75-761-3441 e-mail : [email protected] URL : http://www.urology.kuhp.kyoto-u.ac.jp/

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We take charge of surgical treatment for all categories of cardic diseases (ischemic, valvular and congenital) and vascular diseases (aortic and peripheral). Our goal is to improve clinical outcomes not only by refining on the established surgical methods, but also introducing novel concepts evolved from basic researches.

Ryuzo SakataProfessor

Research and EducationWe conduct patients-oriented researches which are directed toward patients' clinical benefit. Our main topic is the development of novel therapeutic methods for end-stage heart failure. Under this topic, we are undergoing experiments concerning heart transplantation, assist circulation, myocardial regeneration, myocardial protection and therapeutic angiogenesis. Collaboration is actively carried out with Frontier Science Research Institute, Translational Research Center, Other Universities and Centers. We also focus on translational researches. Based on animal experiments, we are conducting clinical trial of therapeutic angiogenesis to treat limb ischemia by sustained release of bFGF using gelatin hydrogel. We convinced that the experiences of the basic research and the ability to solve problems help young surgeons in their further clinical training.

Recent Publications1. Bir SC, Esaki J, Marui A, Sakaguchi H, Kevil CG, Ikeda T, Komeda M, Tabata Y, Sakata R.

Therapeutic Treatment with Sustained-Release Platelet-Rich Plasma Restores Blood Perfusion by Augmenting Ischemia-Induced Angiogenesis and Arteriogenesis in Diabetic Mice. J Vasc Res. 2010;48:195-205

2. Yanagi S, Matsumura K, Marui A, Morishima M, Hyon SH, Ikeda T, Sakata R. Oral pretreatment with a green tea polyphenol for cardioprotection against ischemia-reperfusion injury in an isolated rat heart model. J Thorac Cardiovasc Surg. 2011;141:511-7

3. Muranaka H, Marui A, Tsukashita M, Wang J, Nakano J, Ikeda T, Sakata R. Prolonged mechanical unloading preserves myocardial contractility but impairs relaxation in rat heart of dilated cardiomyopathy accompanied by myocardial stiffness and apoptosis. J Thorac Cardiovasc Surg. 2010:916-22

4. Morishima M, Marui A, Yanagi S, Nomura T, Nakajima N, Hyon SH, Ikeda T, Sakata R. Sustained release of vancomycin from a new biodegradable glue to prevent methicillin-resistant Staphylococcus aureus graft infection. Interact Cardiovasc Thorac Surg. 2010;11:52-5

5. Shimamoto T, Marui A, Nagata Y, Sato M, Saito N, Takeda T, Ueda M, Ikeda T, Sakata R, Inoue K. A novel approach to prevent spinal cord ischemia: Inoue stent graft with a side branch of small caliber for the reconstruction of the artery of Adamkiewicz. J Thorac Cardiovasc Surg. 2010;139:655-9

❶ Scene in the operating room. Cooperation with cardiologists, anesthesiologist, and co-medicals yields excellent surgical results.

❷ Various aspects of cardiovascular surgery. (Left) Left ventricular repair for severely failing heart. (Upper middle) Off-pump CABG has expanded the surgical indication for coronary reconstruction. (Lower middle) obotic surgery is expected to play an important role in the near future. (Right) Cell transplantation for heart failure is one of our researches on the regenerative therapy.

❸ Clinical and Laboratory staffs

Cardiovascular SurgeryProfessor : Ryuzo Sakata Associate Professor : Tadashi Ikeda Senior Lecturer : Senri Miwa Assistant Professor : Kazuhiro Yamazaki, Kenji Minakata, Tomohiro Nakata, Hiroyuki Muranaka AssociateProfessor (Translational Research Center) : Akira Marui AssistantProfessor (Translational Research Center) : Shigeki Yanagi TEL : +81-75-751-3780 FAX : +81-75-751-3098 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Department of Thoracic Surgery, Kyoto University, was founded in 1941 and involved into a leading international thoracic surgery program from one of the earliest such programs in Japan. Clinically, we are dealing with various diseases of the lung and mediastinum. For increasing lung cancer surgery, video-assisted thracoscopic surgery has become a standard approach in our department. A new Kyoto Lung Transplant Program was developed by Professor Date who had done a majority of lung transplants in Japan. Between June 2008 and December 2009, the new program performed living-donor lobar lung transplantation in eight sick patients resulting in all success. We have accepted a number of foreign visitors for observing such operation. Thoracic surgeons trained in our department are practicing in affiliated hospitals mainly in the west part of Japan. Over 2,300 cases of lung cancer surgery (about 10% of cases in whole Japan) are performed annually by our group. Hiroshi Date, M.D., Ph.D.

Professor

Research and EducationFaculty research within the Department of Thoracic Surgery encompasses a wide range of interests including lung cancer, lung transplantation and regenerative medicine. For lung cancer research, we are looking for prognostic factors after lung cancer surgery using specimens removed in OR. Especially, EGFR mutations and EML4-ALK fusion gene have been extensively investigated in our laboratory. Preoperative as well as postoperative chemotherapy and/or chemo-radiotherapy for lung cancer have been studied both in the clinic and in the laboratory so as to identify useful biological makers for “order made treatment”. For lung transplant research, we have developed ET-Kyoto solution for preservation and this solution is now clinically used in various institutions. We are conducting studies on lung transplantation from donors after cardiac death using an ex-vivo lung perfusion animal model. We have found that forced oscillation technique may be useful in detecting rejection after lung transplantation. We first successfully performed a bilateral native lung sparing living-donor lobar lung transplantation which can be applied to large adult recipients. The Department of Thoracic Surgery provides education and treatment of the full range of complex general thoracic problems regarding diagnoses, examinations and surgical and non-surgical therapies.

Recent Publications1. Date H, et al. Improved survival after living-donor lobar lung transplantation. J Thorac Cardiovasc

Surg 128:933-40, 2004 2. Chen F, et al. Prognositc factors of pulmonary metastasectmy for osteosarcomas of the extrimities.

Eur J Cardiovasc Surg 34:1235-9, 2008 3. Satoda N, et al. Value of FOXP3 expression in peripheral blood as rejection maker after miniature

swine lung transplantation. J Heart Lung Transplant 27:1293-301, 2008 4. Date H. Diagnostic strategies for mediastinal tumors and cysts. Thorac Surg Clin 19:29-35, 2009 5. Iwakiri S, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic

recurrence in pathological stage I nonsamll cell lung cancer. Cancer 115:2580-93, 2009 6. Takahashi T, et al. Clinicopathologic feasures of non-small-cell lung cancer with EML4-ALK

fusion gene. Ann Surg Oncol 2009 (Epub ahead of print)

❶ Lung transplantation ❷ Bilateral native lung sparing living-donor lobar lung transplantation ❸ Ex-vivo lung perfusion model ❹ Novel EML4-ALK variants ❺ Department picture

Thoracic SurgeryProfessor : Hiroshi Date Associate Professor : Zhenglong Huang Senior Lecturer : Hiroaki Sakai, Makoto Sonobe Assistant Professor : Tsuyoshi Shoji, Fengshi Chen, Toshihiko Sato TEL : +81-75-751-4975 FAX : +81-75-751-4974 e-mail : [email protected] URL : http://www.thoracic-kyoto-u.gr.jp/

Thoracic Surgery

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Plastic and reconstructive surgery is a specialized branch of surgery to repair deformities and defects of the integument and underlying musculocutaneous framework. In our field, we not only conduct clinical studies for improvement of surgical outcomes but also focus on basic research into wound healing and microcirculation of the skin and subcutaneous tissue. In addition, we had already begun to study skin regeneration before the phrase “regenerative medicine” became popular. One of our achievements in this area has already been commercialized. As well as skin regeneration, we have been studying regeneration of nerve, bone, cartilage and blood vessel. We will continue to perform clinically useful research.

Shigehiko Suzuki, M.D., Ph.D.Professor

Research and EducationCurrent research activities in our field deal with clinical studies regarding maxillofacial surgery, microsurgery, skin surgery and hand surgery, and basic studies regarding regenerative medicine, wound healing, cutaneous microcirculation and embryology.In regenerative medicine, we first started to develop an artificial dermis in cooperation with the Institute for Frontier Medical Sciences. The artificial dermis composed of collagen sponge is spontaneously converted into a synthesized connective tissue matrix similar to the true dermis. The present version of our artificial dermis has been clinically used in the world. In addition, we have developed a new artificial dermis that can provide sustained release of cell growth factors and an autologous cultured dermal substitute containing autologous fibroblasts. These are now in clinical trials in cooperation with Translational Research Center, Center for Cell & Molecular Therapy and the department of dermatology. Furthermore, we have been conducting research on skin-derived precursor cells (SKPs) and the regenerative mechanism of elastic fibers with a view to developing an ideal cultured skin. In addition, we have been studying preservation of the skin and skin substitutes. As for regeneration of cartilage, we identified progenitor cells in the ear perichondrium and are now developing novel scaffolds for clinical application. Furthermore, we have been engaged in studies on regeneration of the central nervous system, peripheral nerves, cartilage, bone and micro vessels. In wound healing, we are putting a great deal of effort into elucidating the origins of keloid tissue and hypertrophic scars and developing fundamental treatments for these problems. In addition, we have been engaged in preparing iPS cells to clarify the pathogenesis of neurodegenerative and cutaneous diseases in collaboration with CiRA (Center for iPS Cell Research and Application) and the department of neurology. Such basic research is closely related to clinical applications. We regard a clinically useful study as highly important in our field and we are training young researchers to have both scientific and clinical perspectives and to aim at performing creative studies. Recent Publications

1. Morimoto,N.,Takemoto,S.,Kanda,N.,Ayvazyan,A.,Taira,T.,Suzuki,S.:The Utilization of animal product-free media and autologous serum in an autologous dermal substitute culture. J Surg Res. 6 Fed 2010. [Epub ahead of print]

2. Ikeda, M., Naitoh, M., Kubota, H., Ishiko, T., Yoshikawa, K., Yamawaki, S., Kurokawa, M., Utani, A., Nakamura, T., Nagata, K., Suzuki, S.: Elastic fiber assembly is disrupted by excessive accumulation of chondroitin sulfate in the human dermal fibrotic disease, keloids. Biochem. Bioph. Res. Co. 390: 1221-1228, 2009.

3. Takemoto, S., Morimoto, N., Kimura, Y., Taira, T., Kitagawa, T., Tomihata, K., Tabata, Y., Suzuki, S.: Preparation of collagen/gelatin sponge scaffold for sustained release of bFGF. Tissue Eng. 14: 1629-1638, 2008.

4. Kawazoe, T., Kim, H., Tsuji, Y., Morimoto, N., Hyon, S.H., Suzuki, S.: Green tea polyphenols affect skin preservation in rats and improve the rate of skin grafts. Cell Transplantation 17: 203-209, 2008.

5. Morimoto, N., Takemoto, S., Kawazoe, T., Tomihata, Taira, T., Suzuki, S: In vivo culturing of a bilayered dermal substitute with adipo-stromal Cells. J Surg Res. 146: 246-253, 2008.

❶ Immunohistochemical analysis of elastic fiber components in normal skin tissues (a) and keloids (b).

❷ Skin-derived precursor cells (SKPs), which are multipotent progenitor cells, have been isolated from adult human dermis.

❸ Instructors and graduate students of our department.

❹ Tissue engineered cartilage using a novel scaffold (a) and its microscopic appearance (b).

❺ Preparing autologous cultured dermis for clinical trial in Cell Processing Center.

❻ Prepared autologous cultured dermis.

Plastic and Reconstructive SurgeryProfessor : Shigehiko Suzuki Senior Lecturer : Katsuya Kawai, Motoko Naitoh, Naoki Morimoto Assistant Professor : Toshihiro Ishiko, Katsuhiro Yoshikawa TEL : +81-75-751-3613 FAX : +81-75-751-4340 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~keisei/

Plastic and Reconstructive Surgery

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- Clinical Medicine (Core Departments) - Surgery for Sensory and Motor System


Vision is a very important function for human life. The process of vision is very complicated that requires numerous components of eye and brain work together. Our focus in research is to clarify the mechanism of various vision threatening eye diseases and to develop new therapeutic approaches for them. To harmonize the ideas from clinics with good quality research, students must tackle not only in research but also in clinical works. You are qualified to join our department if you have a desire to see the details of eye diseases.

Nagahisa Yoshimura, M.D., Ph.D.Professor

Research and EducationEverything related to vision is theme in our department. Vision is a very important function for human life and our interests of research is to understand underlying mechanisms of ocular diseases and the abnormalities that lead to severe visual loss. Our mission is to carry out high-grade laboratory research through observation and knowledge that can be obtained in the clinics.Eye is a very small organ with the size of around 25mm in diameter. However, the structure and function of the eye is very complicated and many of the pathogenesis of ocular diseases has not been clarified yet. Because of the complexity, eye research requires many kinds of knowledge including not only vascular biology, neural cell biology, molecular cell biology, embryology, anatomy, genetics, but engineering, physics and electrophysiology. It is very exciting to put these knowledge and ideas together to precede eye research.One of the main interests in our laboratory are chorioretinal diseases. On-going projects now are to figure out the detailed mechanism in the development of vascular diseases including age-related macular degeneration and diabetic retinopathy, and retinal vascular regeneration or targeted gene therapy using bone marrow progenitor cells, and an alternate approach to identifying potential therapeutic avenues to treating diseases for which there are currently no effective treatments including retinal degenerative diseases. With industrial partners, recently, we have developed new-generation optical coherence tomography (OCT) and now vigorously working to elucidate the pathophysiology of various chorioretinal diseases with the use of new-generation OCT. It s not easy to do research and clinical work simultaneously, however, we believe that there is something important for clinicians that can be obtained only though intensive research experience. We hope you will join us and share the excitement of eye research.

Recent Publications1. Ooto S, Hangai M, Sakamoto A, Tsujikawa A, Yamashiro K, Ojima Y, Yamada Y, Mukai

H, Oshima S, Inoue T, Yoshimura N. High-resolution imaging of resolved central serous chorioretinopathy using adaptive optics scanning laser ophthalmoscopy. Ophthalmology 117: 1800-1809, 2010

2. Tsujikawa A, Sakamoto A, Ota M, Kotera Y, Oh H, Miyamoto K, Kita M, Yoshimura N. Serous retinal detachment associated with retinal vein occlusion. Am J Ophthalmol 149: 291-301, 2010

3. Mori S, Hangai M, Sakamoto A, Yoshimura N. Spectral-domain optical coherence tomography measurement of macular volume for diagnosing glaucoma. J Glaucoma 19: 528-534, 2010

4. Unoki N, Murakami T, Ogino K, Nukada M, Yoshimura N. Time-lapse imaging of retinal angiogenesis reveals decreased development and progression of neovascular sprouting treated with anecortave desacetate. Invest Ophthalmol Vis Sci 51: 2347-2355, 2010

5. Hayashi H, Yamashiro K, Gotoh N, Nakanishi H, Nakata I, Tsujikawa A, Otani A, Saito M, Iida T, Matsuo K, Tajima K, Yamada R, Yoshimura N. CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 51: 5914-5919, 2010

❶ H i g h - r e s o l u t i o n i m a g i n g o f the photoreceptor layer using adaptive optics scanning laser ophthalmoscopy

❷ Spectral-domain optical coherence tomography (SD-OCT) images of retinal edema associated with branch retinal vein occlusion (Ref.2)

❸ Color-coded maps of scans by which to measure the total retinal volume obtained by SD-OCT in the eye of a patient with glaucoma (Ref.3)

❹ T ime- lapse imaging of ret inal angiogenesis (Ref.4)

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Ophthalmology and Visual SciencesProfessor : Nagahisa Yoshimura Associate Professor : Masanori Hangai Senior Lecturer : Kazuaki Miyamoto, Akitaka Tsujikawa, Atsushi Otani Assistant Professor : Atsushi Nonaka, Kenji Yamashiro, Sotaro Ooto, Tadamichi Akagi, Tomoaki Murakami, Hanako Ikeda, Akio Oishi, Akihito Uji TEL : +81-75-751-3248 FAX : +81-75-752-0933 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~ganka/

Ophthalmology and Visual Sciences

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- Clinical Medicine (Core Departments) - Surgery for Sensory and Motor Systems


Otolaryngology - Head and Neck Surgery treats all disorders in the head and neck field. Therefore we treat the largest number of diseases in the clinical departments. Among diverse diseases, disorders of sensory organs (auditory, vestibular, olfactory, and gustatory) are characteristic of our specialty. The most important problem to overcome is the deafness due to the cochlear hair cell damages. We are mainly working on this project using the methods of regenerative medicine. At the same time, we are working on the project for the regeneration of several organs such as mastoid mucosa, vocal fold, trachea, and recurrent laryngeal nerve, for functional recovery after the deficit by surgery. Clinical application for the novel inner ear treatment using inner ear drug delivery system and for the regeneration of the ear drum and atrophied vocal folds has been started. Another project is to elucidate the central mechanisms of human auditory system using functional brain imaging (MEG, fMRI, and PET). Juichi Ito, M.D., Ph.D.

Professor

Research and Education■Regeneration of inner earOnce damaged, inner ear sensory cells never regenerate and their function do not recover. The purpose of our study is to overcome this difficulty and realize functional regeneration of inner ear. The 43rd Erwin von Bälz prize was awarded to this work. We have been addressing this difficulty using following approaches.1. Stem cell transplantationWe transplant the multipotent stem cells, such as ES cells, iPS cells, bone marrow stromal cells, adipose stem cells etc., into inner ear. Some of grafted cells survived and differentiated into inner ear cells, and partial functional recovery was observed. Our cell transplantation technique is widely highly respected in the field of inner ear research.2. Mechanisms of hearing impairment and the development of the new treatmentSeveral genes that play important roles in the development and function of inner ear has been identified. We investigate the mechanisms of hearing impairment using the knockout mice and model animals to develop the therapeutic application. By manipulating related genes, we successfully induced proliferation of supporting cells that do not usually happen in the inner ear of adult mammals. We also investigate the therapeutic potentials of growth factors and low molecular weight agents for the treatment of hearing.3. Therapeutic application by inner ear drug delivery system (DDS)Using the drug delivery system, we locally apply the trophic factors and therapeutic drugs into the inner ear. This method enables application of drugs without systemic side effects. We have developed the inner ear DDS and conducted the clinical trial using the local application of insulin-like growth factor 1 (IGF-1). The next phase clinical trial is in preparation.■Regeneration of middle ear, trachea, and larynxWe study the way of regeneration of several other organs in the head and neck using the in situ tissue engineering techniques. Transplantation of scaffolds with stem cells enabled the regeneration of larynx, trachea, recurrent laryngeal nerve, and middle ear mucosa.

Recent Publications1. Horie RT, Sakamoto T, Nakagawa T, Ishihara T, Higaki M, Ito J. Stealth-nanoparticle strategy

for enhancing the efficacy of steroids in mice with noise-induced hearing loss. Nanomedicine (London) 5:1331-1340, 2010.

2. Nakagawa T, Sakamoto T, Hiraumi H, Kikkawa YS, Yamamoto N, Hamaguchi K, Ono K, Yamamoto M, Tabata Y, Teramukai S, Tanaka S, Tada H, Onodera R, Yonezawa A, Inui K, Ito J. Topical insulin-like growth factor-1 treatment using gelatin hydrogels for glucocorticoid-resistant sudden sensorineural hearing loss: a prospective clinical trial. BMC Med 8:76, 2010.

3. Kitajiri S, Sakamoto T, Belyantseva I, Goodyear R, Stepanyan R, Fujiwara I, Bird J, Riazuddin Sa, Riazuddin Sh, Ahmed Z, Hinshaw J, Sellers J, Bartles J, Hammer J, Richardson G, Griffith A, Frolenkov G, Friedman T Actin-bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing Cell. 2010 May 28;141(5):786-98.

4. Kishimoto Y, Hirano S, Kitani Y, et al. Chronic vocal fold scar restoration with hepatocyte growth factor. Laryngoscope 2010;120:108-113.

5. Yamashita M, Kanemaru S, Hirano S, et al. Glottal reconstruction with a tissue engineering technique using polypropylene mesh: A canine experiment. Ann Otol Rhinol Laryngol 2010;119:110-117.

❶ Neurally induced ES and iPS cells for transplantation into inner ear ❷ Proliferation of supporting cells were successfully induced by gene manipulation ❸ Surface image of Cochlear outer hair cells ❹ Regeneration of an ear drum using bFGF spongel ❺ Regeneration of the vocal fold using acellular extracellular matrix ❻ Members of inner ear regeneration research ❼ Members of regeneration research of middle ear, traceha and larynx

Otolaryngology-Head and Neck SurgeryProfessor : Juichi Ito Senior Lecturer : Shigeru Hirano, Takayuki Nakagawa Assistant Professor : Ichiro Tateya, Akiko Taura, Harukazu Hiraumi, Tatsunori Sakamoto, Norio Yamamoto, Morimasa Kitamura, Shin-ichiro Kitajiri TEL : +81-75-751-3346 FAX : +81-75-751-7225 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~ent/

Otolaryngology-Head and Neck Surgery

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We, orthopaedic surgeons, treat patients who suffer diseases and injuries in the musculo-skeletal system. Most of the people experience knee or shoulder pain and low back pain in a lifetime. Femoral or vertebral fracture is the second popular cause that leads the elderly people to become bedridden. We believe that overcoming functional disability of the musculo-skeletal system contribute not only to the happiness of an individual patient but also to the welfare of our whole society. The first decade in the 21st century was the “Bone and Joint Decade”, in which the World Health Organization (WHO) promoted the world-wide improvement in the treatment of the musculo-skeletal disorders. We hope that all people can mobilize their healthy body without difficulties through their life.

Takashi Nakamura, MD, D.M.Sc.Professor

Research and EducationClinical and basic researches are carried out intensively and vigorously in each group of specialists. We deal with many joint disease including hip joint diseases (osteoarthritis of the hip, avascular necrosis of the femoral head, etc), knee joint diseases (osteoarthritis of the knee, ligament injury, meniscal injury, etc), and other joint disease, rheumatoid diseases like rheumatoid arthritis. We also treat spinal diseases (disc herniation, ossification of the posterior longitudinal ligament, spinal tumors, etc), bone and soft tissue tumors (osteosarcoma, liposarcoma, etc), disorders in the upper extremity (amputated fingers, peripheral nerve palsy, etc), and so forth. Our department consists of 6 groups; hip surgery, sports medicine and knee/shoulder surgery, rheumatology, spine surgery, musculo-skeltal tumor surgery, and hand surgery. Each group has clinical conference and/or journal club at least once a week, where the surgeons heighten and refresh their clinical and surgical skills. We also try frontier diagnosis and treatment as members of world leading university.We are also doing basic research working with post-graduate students and clinical fellows. Skeletal formation/functional regulation group is focusing on genome-wide and systemic analyses of gene and protein expression, function in skeletogenesis and bone and cartilage metabolism using molecular biological, biochemical, and mouse genetics approaches. Biomaterial group has developed many bioactive implants, some of which have been applied clinically. Recently good osteoconductive and osteoinductive titanium has been developed. Using this material, a new spinal fusion cage was made and used in patients as a clinical trial, with an excellent result. Tumor group is researching on a molecular mechanism of generation of bone and soft tissue tumor and its application to clinical cases. Application of bone marrow stromal cells to necrotic lesion of femoral head or carpal bone is under clinical research, collaborated with Institute for Frontier Medical Science. Cartilage metabolism/rheumatology group is experimentally investigating the mechanism of joint destruction in osteoarthritis and rheumatoid arthritis, leading to future cartilage repair. Sports medicine and knee/shoulder surgery group is developing imaging systems in order to evaluate physical and structural properties of the cartilage for clinical applications. Peripheral nerve group is working on the nerve regeneration, once thought impossible, trying to apply the method for treating nerve degeneration and injury. Recent Publications

1. Ikeguchi R, Kakinoki R, Aoyama T, Shibata KR, Otsuka S, Fukiage K, Nishijo K, Ishibe T, Shima Y, Otsuki B, Azuma T, Tsutsumi S, Nakayama T, Otsuka T, Nakamura T, Toguchida J,:Regenerartion of osteonecrosis of canine scapho-lunate using marrow stromal cells: possible therapeutic approach for Kienbock disease:Cell Transplant:15,5: 411-22:2006

2. Takemoto M, Fujibayashi S, Neo M, So K, Akiyama N, Matsushita T, Kokubo T, Nakamura T,:A porous bioactive titanium implant for spinal interbody fusion: an experimental study using a canine model:J Neurosurg Spine:4:435-43:2007

3. Kimura H, Kwan KM, Zhang Z, Deng JM, Darnay BG, Behringer RR, Nakamura T, Crombrugghe B, Akiyama H,:Cthrc1 is a positive regulator of osteoblastic bone formation:PLoS ONE:3,9:e3174:2008

4. Miyata M, Neo M, Fujibayashi S, Ito H, Takemoto M, Nakamura T,:O-C2 angle as a predictor of dyspnea and/or dysphagia after occipitocervical fusion:Spine (Phila Pa 1976) :34,2:184-8:2009

5. Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, Nakano M, Fujii N, Nagasawa T, Nakamura T, :Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model:Arthritis Rheum:60,3:813-23:2009

6. Kawanabe K, Ise K, Goto K, Akiyama H, Nakamura T, Kaneuji A, Sugimori T, Matsumoto T,:A new cementless total hip arthroplasty with bioactive titanium porous-coating by alkaline and heat treatment: average 4.8-year results:J Biomed Mater Res B Appl Biomater:90,1:476-81:2009

❶ Navigation system is used in a difficult operation in spine surgery as well as artificial joint surgery. (Reference1)

❷ Newly developed cementless total hip joint system (left) and canine spinal fusion using bioactive porous titanium (right). (Reference2, 3)

❸ Clinical application of bone marrow stromal cell to necrotic lesion of femoral head or hand. (left: treatment, right: non-treatment) (Reference4)

❹ Skeletogenesis and bone and cartilage metabolism by molecular biological, biochemical, and mouse genetics approaches. (Reference5)

❺ Staff of orthopedic surgery

Orthopaedic and Musculoskeletal SurgeryProfessor : Takashi Nakamura Associate Professor : Masashi Neo, Haruhiko Akiyama Senior Lecturer : Tomitaka Nakayama, Masahiko Kobayashi Assistant Professor : Hiromu Ito, Shunsuke Fujibayashi, Takeharu Nakamata, Takeshi Okamoto, Hiroyuki Yoshitomi, Tadashi Goto, Mitsuru Takemoto, Koji Yamamoto TEL : +81-75-751-3652 FAX : +81-75-751-8409 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Orthopaedic and Musculoskeletal Surgery

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Department of Oral and Maxillofacial Surgery is committed with academic oral surgeon aiming to progress the clinical care, education, and scientific research. Our mission is to advance the modern diagnosis and treatment for dent-maxillofacial, oral and craniofacial disorders through innovative basic and clinical research. Based on Kyoto University’s highest intellectual and physical resources, we are maintaining the top level of patient’s care, residency and postgraduate education program, and frontier research.

Kazuhisa Bessho, D.D.S.,D.M.Sc.Professor

Research and EducationThe current researches in our department are as follows.Our major interest is to clarify the mechanisms of the onset of temporomandibular joint disorders (TMDs), especially "closed lock". In previous studies, our research unit has evaluated histopathologic and biochemical alterations of temporomandibular arthritis induced by mechanical loading in rabbits (arthritis animal models), because excessive loads on the glenoid fossa is thought one of the significant causes of TMDs. Also our research unit has analyzed concentration of proteins and cytokines in the synovial fluids of TMD patients. Now we have interest in methodologies of mass spectrometric analysis of hyaluronic acid in synovial fluids. Our research unit is analyzing normal and abnormal jaw function through refined recordings of muscle activity and jaw movement in 3 dimensional magnetic resonance imaging (MRI) and high speed MRI (HASTE method: figure ) for studying the detailed functions of the jaw muscles. These same methodologies are being applied to the study of jaw function in TMD patients to identify differences between TMD patients and normal persons. We think the outcomes from these studies should lead to a reduction of the burden that TMD causes on the medical practice. Uterine sensitization associated gene-1 (USAG-1) is a BMP antagonist that functions in the local regulation of BMP mediated signal transduction by binding and neutralizing BMP activities, and also modulates Wnt signaling . We previously reported that USAG-1 deficient mice have supernumerary teeth. The supernumerary maxillary incisor appears to form as a result of the successive development of the rudimentary upper incisor. USAG-1 abrogation rescued apoptotic elimination of odontogenic mesenchymal cells. We confirmed that BMPs were expressed in both the epithelium and mesenchyme of the rudimentary incisor at E14 and E15. BMP signaling in the rudimentary maxillary incisor, assessed by expressions of Msx1 and Dlx2 and the phosphorylation of Smad protein, was significantly enhanced. Inhibition of BMP signaling rescues supernumerary tooth formation in E15 incisor explant culture. Based upon these results, we conclude that enhanced BMP signaling results in supernumerary teeth in the USAG-1 deficient mouse model. We constructed a BMP-2-expressing adenoviral vector with high efficiency and succeeded gene transfer by electroporation and sonoporation with a BMP-2-expressing plasmid vector. These bone regeneration methods may be useful in clinic. The pluripotential cells isolated from the pulp of human teeth and expanded in vitro, differentiated into osteoblasts, chondrocytes and adipocytes. We research about biomaterials and bone reconstruction using bone morphogenetic protein expressing vector. And we examine interactions between osteoinduction and chemicals. On the other hand, we research and develop new diagnosis devices, operation devices and dental implant in cooperation with Faculty of Engineering and enterprises.

Recent Publications1. Takafuji H, Suzuki T, Okubo Y, Fujimura K, Bessho K. Regeneration of articular cartilage defects

in the temporomandibular joint of rabbits by fibroblast growth factor-2.Int J Oral Maxillofac Surg. 36, 934-937, 2007.

2. Takahashi, K., Sakata, T., Murashima-Suginami, A., Tsukamoto, H., Kiso, H., Bessho, K. Tooth regeneration: Potential for stimulation of the formation of a third dentition by one gene, Current Topics in Genetics, 3, 77-82, 2008

3. Osawa K, Okubo Y, Nakao K, Koyama N, Bessho K. Osteoinduction by repeat plasmid injection of human bone morphogenetic protein-2. J Gene Med. 12, 937-944, 2010

4. Kaihara S, Bessho K, Okubo Y, Sonobe J, Kawai M, Iizuka T. Simple and effective osteoinductive gene therapy by local injection of a bone morphogenetic -2-expressing recombinant adenoviral vector and FK506 mixture in rats. Gene Therapy. 11:439-447, 2004

5. Yamori M, Yoshida M, Watanabe T, Shirai Y, Iizuka T, Kita T, Wakatsuki Y Antigenic activation of Th1 cells in the gastric mucosa enhance dysregulated apoptosis and turnover of the epithelial cells. Biochem Biophys Res Commun. 316:1015-1021, 2004

❶ High speed MRI (HASTE)Left: Anterior displacement of disc without reduction

❷ Osteoinduction by bone morphogenetic protein us ing t ranscutaneous sonoporation.

❸ Supernumerary maxillary incisor in USAG-1 deficient mouse

❹ Osteoinduction in the calf muscle of rat by bone morphogenetic protein-2-expressing recombinant adenoviral vector.

❺ The research on the links between oral health and general health

❻ Staffs

Oral and Maxillofacial SurgeryProfessor : Kazuhisa Bessho Associate Professor : Kazuma Fujimura Senior Lecturer : Katsu Takahashi, Junya Sonobe Assistant Professor : Kazuhisa Goto, Masashi Yamori, Hiromitsu Yamamoto TEL : +81-75-751-3401 FAX : +81-75-761-9732 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/%7E

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Oral and Maxillofacial Surgery

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Few areas of medicine remain unaffected by the rapid developments in molecular genetics that have taken place over recent years. Not only the classic Mendelian disorders, but also diseases of complex and multifactorial etiology are now susceptible to investigation at the molecular level. Moreover, gene therapies are expected to become important therapeutic modalities in the 21st century. To apply molecular medicine to the clinics, however, there are still many problems. We need hard-working, motivated individuals to work with us to resolve them.

Jun Fujita, M.D., Ph.D.Professor

Research and EducationHepatocellular carcinoma (HCC) is a common and aggressive malignant tumor with especially high prevalence in Asia and Africa. Many are diagnosed with advanced HCC and have little chance of survival. To improve diagnosis and identify therapeutic targets for the treatment of HCC patients, we have isolated several genes overexpressed in HCC such as novel genes gankyrin and HSCO. Since gankyrin was overexpressed in all HCC analyzed, we have been developing therapeutic agents based on its structure or functions. Compared to bacteria and plants, the cold shock response has attracted little attention in mammals. Although previous studies have mostly dealt with temperatures below 20°C, we are interested in mild cold (32°C), and have shown that it can change the cell's response to subsequent stresses. Furthermore, we have identified the first cold shock protein, Cirp, in mammalian cells at 32°C. We have identified more mammalian cold shock proteins, and have been clarifying the regulatory mechanisms of mild-cold response. Mammalian cells are metabolically active and respond to stresses at 32°C with strategies different from those at 37°C. Genetic counseling has been impacted by the rapid increase in information. To gain easy access to the expanding and useful clinical genetics resources, we have started an internet site, “Iden-Net”. Among its contents, most noteworthy will be the computerized directory of Japanese laboratories performing disease-specific DNA testing of heritable disorders and the directory of Japanese genetic counselors.

Recent Publications1. Higashitsuji, H., Itoh, K., Nagao, T., Dawson, S., Nonoguchi, K., Kido,T., Mayer, R.J., Arii, S.,

Fujita, J. (2000) Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nature Med., 6, 96-99.

2. Higashitsuji, H., Higashitsuji, H., Nagao, T., Nonoguchi, K., Fujii, S.,Itoh, K., Fujita, J. (2002) A novel protein overexpressed in hepatoma accelerates export of NF-_B from the nucleus and inhibits p53-dependent apoptosis. Cancer Cell, 2, 333-346.

3. Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Nagao T, Sumitomo H,Masuda T, Dawson S, Shimada Y, Mayer RJ, Fujita J.(2005) The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell, 8, 75-87.

4. Higashitsuji, H., Higashitsuji ,H., Masuda, T., Liu, Y., Itoh, K.,Fujita, J. (2007) Enhanced deacetylation of p53 by the anti-apoptotic protein HSCO in association with HDAC1. J. Biol. Chem., 282, 13716-13725.

5. Fujita, J. (2008) Gankyrin. in Encyclopedia of Cancer, 2nd ed. Schwab M(ed), pp1205-1207, Springer, Berlin.

❶ S t r u c t u r e o f g a n k y r i n . O r t h o g o n a l r i b b o n representations of gankyrin. The polypeptide chain is color-ramped from its N terminus in blue to the C terminus in red.

❷ Delivering polyubiquitylated s u b s t r a t e s t o t h e 2 6 S proteasome.

Gankyrin probably delivers ubiquitylated p53 to the p ro teasome by b ind ing to MDM2 as well as the S6b subuni t o f the 26S proteasome.

❸ Temperature-dependent expression of cirp mRNA in BALB/3T3 cells.

❹ Members of the laboratory.

Clinical Molecular BiologyProfessor : Jun FUJITA Associate Professor : Katsuhiko ITOH Assistant Professor : Hiroaki HIGASHITSUJI, Hisako HIGASHITSUJI TEL : +81-75-751-3751 FAX : +81-75-751-3750 e-mail : [email protected]

Clinical Molecular Biology

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- Clinical Medicine (Core Departments) - Medical Genetics


Department of Neurology have served as an academic research center by educating students, residents, and staff towards professional values in neurosciences; neuropathology, neurochemistry, molecular neurobiology, and neurophysiology using molecular biology, molecular genetics, developmental engineering, pharmacology, electrophysiology, histology, and/or system brain science to achieve novel and efficient therapies for intractable neurological diseases.

Ryosuke Takahashi, M.D. Ph.D.Professor

Research and EducationDepartment of Neurology consists of 4 laboratories.In Neuropathology lab, we examine human autopsy brains in clinico-pathological conference, and further study with immunohistochemistry and neurochemical methods. Using genetically-modulated animals, we are doing research work on the pathogenesis and new therapeutic strategies for stroke and dementia, and neurodegenerative diseases (Figure 1).In Neurochemistry lab, we study the molecular mechanism of neuronal death in neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS), and are trying to develop novel therapy for the diseases. For example we have revealed the nicotinic receptor-mediated neuroprotective cascade (Figure 2). Moreover, we study proteomics to investigate the pathogenesis and develop diagnostic methods in neurodegenerative disorders. Molecular Neurobiology lab aims to provide novel preventive/therapeutic approaches towards sporadic Parkinson’s disease and ALS based on recent findings that misfolded proteins cause neurodegeneration either in familial Parkinson’s disease or familial ALS (Figure 3). In Neurophysiology lab, we have aimed at elucidating the pathophysiology of the diseases of the central nervous systems involving the neuronal circuitry and functional organization such as epilepsy, movement disorders and higher cortical dysfunctions, and at promoting the new treatment approaches. We also have clarified the mechanism of higher cortical functions in humans such as motor control, language and sensory perception, all of which are always related to the relevant diseases (Figure 4). For education, we provide students and residents with organized, educational course of researches.

Recent Publications1. Imai, Y., Soda, M., Inoue, H., Hattori, N., Mizuno, Y. and Takahashi, R. An unfolded putative

membrane transmembrane olypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891-902, 2001.

2. Kinoshita, M., Ikeda, A., Matsumoto, R., Begum, T., Usui, K., Yamamoto, J., Matsuhashi, M., Takayama, M., Mikuni, N., Takahashi, J., Miyamoto, S., and Shibasaki, H. Electric stimulation on human cortex suppresses fast cortical activity and epileptic spikes. Epilepsia 45: 787-791, 2004.

❶ Neuropathology lab accumulated 360 brains with a variety of neurological diseases. These disease include cerebrovascular diseases, infection, tumor, neurodegenerative and demyelinating diseases. The brains are subjected to clinicopathological conference and examination with immunohistochemical and neurochemical methods.

❷ Nicotinic receptor-mediated neuroprotection against apoptosis.

NeurologyProfessor : Ryosuke Takahashi Associate Professor : Akio Ikeda Senior Lecturer : Hidefumi Ito Assistant Professor : Riki Matsumoto, Kengo Uemura, Masafumi Ihara, Makio Takahashi, Hirofumi Yamashita TEL : +81-75-751-4397 FAX : +81-75-761-9780 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/%7

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Neurology

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- Clinical Medicine (Core Departments) - Clinical Neuroscience


As the advance of neuroscience, neurosurgery has developed into a division of neuroscience from the specialized field concerned with the diagnosis and treatment of disorders or injuries in the brain, spinal cord or peripheral nerves. Our department is characterized as high activity in clinical science, a faculty to develop innovative treatments based on neuroscience, and establishments of medical evidence for the management of nervous system and neurovascular disorders. We also collaborate with basic research laboratories and apply its results into the clinical field. This scientific approach is also of great advantage to the education system in neurosurgery.

Susumu Miyamoto, M.D., Ph.D.Professor

Research and EducationClinical ResearchOur department plays a major role in the nationwide clinical studies of moyamoya disease, unruptured cerebral aneurysm, hemodynamic brain ischemia and brain tumors. To preserve the patient’s brain function, we advance the surgical technique and operation system using awake-craniotomy and functional brain mapping. Our clinical research has developed on the base that we are in possession of microsurgical training system, abundant clinical experience and many experts in neurosurgical subspecialty. Basic ResearchIn the neurovascular laboratory, we investigate susceptible genes for the familial intracranial aneurysms, arteriovenous malformation and moyamoya disease. Using animal models of cerebral aneurysms, we have shown that cerebral aneurysm formation is based on the chronic vascular inflammation. Recently, the studies of risk factor for ischemic stroke and the instrument to evaluate arteriosclerosis noninvasively have launched. In the brain tumor laboratory, we are currently focusing to determine the molecular mechanism of glioma growth and invasion using in-vivo imaging system with two-photon microscope, epigenetic regulation of brain tumor stem cell, and molecular diagnosis of glioma. We also try to establish oncolytic therapy with vaccinia virus. In the brain functional laboratory, we develop methodology for human brain imaging with high-resolution 3-tesla MRI and magnetoencephalography (MEG) and intraoperative brain functional mapping and monitoring. In the neuronal regeneration laboratory, we challenge to establish the regeneration treatment for Parkinson disease and brain ischemia using ES cells and iPS cells. We also study the bHLH factor regulation in pituitary gland generation and new artificial materials useful for neurosurgical treatments. EducationOur department has improved the education system for young neurosurgeon by collaborating with the related hospitals. Our aim is that a trainee rapidly acquires the skill necessary to microsurgery and endovascular treatment through plenty of clinical experience and skill training in the laboratory. Furthermore, there are opportunities to learn techniques of neurosurgical subspecialty in the related hospital, such as spine surgery, pediatric neurosurgery and endovascular surgery. In the Ph.D. course, the student attends to basic research applicable to neurosurgical fields, which will add his/her ability to think scientifically at clinical work. All young neurosurgeon also has a chance to receive their skill training in the domestic and foreign institutes. The goal is that we provide a neurosurgeon with high-level skill as well as makings of a leader in neurosurgical field.

Recent Publications1. Iihara K, Murao K, Yamada N, Takahashi JC, Nakajima N, Satow T, Hishikawa T, Nagata I,

Miyamoto S. Growth potential and response to multimodality treatment of partially thrombosed large or giant aneurysms in the posterior circulation. Neurosurgery 2008; 63(5):832-42.

2. Ogawa A, Mori E, Minematsu K, Taki W, Takahashi A, Nemoto S, Miyamoto S, Sasaki M, Inoue T; MELT Japan Study Group. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke. 2007;38(10):2633-9.

3. Mikuni N, Okada T, Nishida N, Taki J, Enatsu R, Ikeda A, Miki Y, Hanakawa T, Fukuyama H, Hashimoto N. Comparison between motor evoked potential recording and fiber tracking for estimating pyramidal tracts near brain tumors. J Neurosurg. 2007; 106(1):128-33.

4. Hayase M, Kitada M, Wakao S, Itokazu Y, Nozaki K, Hashimoto N, Takagi Y, Dezawa M. Committed neural progenitor cells derived from genetically modified bone marrow stromal cells ameliorate deficits in a rat model of stroke. J Cereb Blood Flow Metab. 2009.

5. Aoki T, Kataoka H, Ishibashi R, Nozaki K, Morishita R, Hashimoto N. Reduced Collagen Biosynthesis Is the Hallmark of Cerebral Aneurysm. Contribution of Interleukin-1{beta} and Nuclear Factor-{kappa}B. Arterioscler Thromb Vasc Biol. 2009

6. Hirata E, Arakawa Y, Shirahata M, Yamaguchi M, Kishi Y, Okada T, Takahashi JA, Matsuda M, Hashimoto N. Endogenous tenascin-C enhances glioblastoma invasion with reactive change of surrounding brain tissue. Cancer Sci. 2009

❶ Maximum flow reduction (MFR) strategy for large thrombosed aneurysms. ❷ Brain functional study with high-resolution 3-tesla MRI ❸ Clinical application of the artificial dura mater made of absorptive material. ❹ Oncolytic therapy with vaccinia virus: vaccinia virus (green) and actin filament (red). ❺ Induction of neuronal cells from ES cells.

NeurosurgeryProfessor : Susumu Miyamoto Senior Lecturer : Jun Takahashi, Taketo Hatano Assistant Professor : Yoshiki Arakawa, Akira Ishii, Masanobu Okauchi, Kazumichi Yoshida, Masato Hojo TEL : +81-75-751-3450 FAX : +81-75-753-9501 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Neurosurgery

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The Department of Psychiatry was established in September 1902, just 100 years ago. From then onward, our Department has continued to play an important role as a clinical research center for psychiatry in Japan, in particular, in the realms of psychopathology, neuropsychology, neuropathology, child and forensic psychiatry. We will uphold this tradition and continue to go ever further. However, psychiatry is also related to the recently rapid developments in brain science. Currently, various techniques from brain imaging to a gene analysis are being used in psychiatric research. We will actively conduct these biological studies in order to elucidate the etiology or pathogenesis of psychoses and find new treatment techniques.

Toshiya MuraiProfessor

Research and EducationBy applying neurobiological as well as psychosocial approaches flexibly, we aim to achieve a multi-faceted understanding of psychiatric disorders.1)NeuroimagingImpa i rmen t o f soc ia l cogn i t ion , dec i s ion making, and social behaviors are common in various neuropsychiatric conditions. Multimodal neuroimaging, including functional MRI and high resolution gray and white matter imaging, is applied to elucidate the neural correlates of these processes. 2) PsychopathologyPsychopathology, which attempts to directly understand the psychology underlying mental phenomena, is one of the essential approaches to investigation of psychiatric diseases. Especially, we focus on eating disorders, dissociative disorders and psychiatric aspects of epilepsy. Psychiatric issues of patients and donors of living organ transplantation are also studied.3)NeuropsychologyIn co l l abora t ion wi th b ra in su rgeons and occupational and speech therapists, neural correlates of cognitive and behavioral sequelae after brain damage are investigated. Especially, we attempt to elucidate the mechanisms and possible therapeutic approaches for alterations of social behaviors after traumatic brain injury4) Child and Adolescent PsychiatryWe are currently focusing on the following themes on developmental disorders in children and adolescents: variability of diagnostic assessments; relationships between phenotype and neurocognitive functions; effectiveness of each intervention; and factors predicting outcome. 5)Forensic psychiatryWe tackle issues of criminal responsibility and civil competency of individuals with mental disorders. Especially, biological and psychosocial mechanisms of violence as well as the predictability of a return to criminal behavior after treatment or release from incarceration are investigated by combining multi-disciplinary approaches.

Recent Publications1. Hirao K, Miyata J, Fujiwara H, Yamada M, Namiki C, Shimizu M, Sawamoto N, Fukuyama H,

Hayashi T, Murai T. Theory of mind and frontal lobe pathology in schizophrenia: A voxel-based morphometric study. Schizophrenia Research 105:165-74, 2008.

2. Miyata J, Hirao K, Namiki C, Fujiwara H, Shimizu M, Fukuyama H, Sawamoto N, Hayashi T, Murai T. Reduced white matter integrity correlated with cortico-subcortical gray matter deficits in schizophrenia. Schizophrenia Research 111:78-85, 2009.

3. Ueda K, Fujiwara H, Miyata J, Hirao K, Saze T, Kawada R, Fujimoto S, Tanaka Y, Sawamoto N, Fukuyama H, Murai T. Investigating association of brain volumes with intracranial capacity in schizophrenia. Neuroimage 49:2503-8, 2010.

4. Noma S, Hayashi A, Uehara M, Kuwabara H, Tanaka S, Furuno Y, Ogawa K, Hayashi T. Psychosocial predictors of psychiatric disorders after living donor liver transplantation. International Journal of Psychiatry in Clinical Practice 12:120-126, 2008.

5. Okada T, Sato W, Kubota Y, Usui K, Inoue Y, Murai T, Hayashi T, Toichi M. Involvement of medial temporal structures in reflexive attentional shift by gaze. Soc Cogn Affect Neurosci 3:80-88, 2008.

PsychiatryProfessor : Toshiya Murai Senior Lecturer : Shun'ichi Noma, Takashi Okada, Hidehiko Takahashi Clinical Lecturer : Kenjiro Fukao Assistant Professor : Akira Oshita, Taro Suwa, Nobuyuki Yamasaki, Jun Miyata, Keita Ueda, Yasuko Funabiki TEL : +81-75-751-3386 FAX : +81-75-751-3246 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Psychiatry



Former department was fully restructured in 2002 as a new Department of Transfusion Medicine and Cell Therapy along with the rapid progress of medicinal science elucidating new molecular and cellular pathophysiology of incurable diseases such as cancers. In addition to control transfusion therapy in the hospital, we supply purified hematopoietic stem cells and relevant cells to clinical trials for allogeneic bone marrow, peripheral blood, and cord blood transplantations. Our research and clinical goals are to develop innovative cell therapy, regenerative therapy, and molecular target therapy for leukemias and other malignancies. Stem cell transplantation, cell and regenerative therapy, and molecular target therapy being ultimate therapeutic approaches for incurable diseases, their establishments (translational research) are urgently needed. To provide clinical-graded therapeutic human cells for translational trials, GMP-graded cell processing facility (Center for Cell and Molecular Therapy: CCMT, Fig.1) has been established in 2003 next door to the Department. Therefore, the Department of Transfusion Medicine and Cell Therapy will play the pivotal role in new era for the progress of advanced medical research and clinical trials at Kyoto University Hospital.

Taira Maekawa, M.D., D.Med. Sci.Professor

Research and EducationThis department is responsible for education concerning transfusion medicine for undergraduate and graduate students, and also has to supervise appropriate use of blood products for transfusion therapy in the university hospital. In addition, to improve the clinical outcome of hematopoietic stem cell transplantation and cell therapy, we provide qualified and powerful therapeutic human cells and tissues to the clinical settings and develop novel method to detect anti-ABO, and anti-HLA antibodies (Fig 2). Recently we have successfully performed allogeneic islet cell transplantation to a patient with severe type I diabetes from a related living donor for the first time in the world. In addition to these cellular therapy, we have been engaged in basic and clinical researches involving molecular target therapy for cancer. We are now working on the following three main projects; a) imatinib mesylate, a competitive inhibitor of Abl tyrosine kinase, is highly effective, but remissions induced in advanced phase CML and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia tend to be relatively short-lived mostly due to point mutations within the Abl kinase domain. New tyrosine kinase inhibitors have been developed to override such resistance. We developed INNO-406, which is one of these new compounds and phase I clinical trial has been successfully, and has named bafetinib and multi-kinase inhibitor, AT9283 (Fig.3) , b) RNA interference, which has recently been introduced into cancer therapy, is a newly discovered cellular pathway for silencing genes at the mRNA level in a sequence-specific manner by the introduction of small interfering RNA (siRNA)(Fig.4), c) γδT cells kill myeloma cells by recognizing metabolites of the mevalonate pathway and ICAM-1 on the myeloma cells. This suggests that patients with myeloma cells that express high levels of ICAM-1 are suitable for cellular immunotherapy usingγδT cells in a clinical setting (Fig.5). We are also interested in the transcriptional system of granulopoiesis and in the control of GvHD using mesenchymal stem cells, and trying to bring it into translational research. Young investigators and graduate students with curious and challenging mind are always very welcome (Fig.6).

Recent Publications1. Takeuchi M et al. (2011) Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl

positive leukemic cells. Cancer Sci, in press. 2. Tanaka R et al. (2010) Activity of the multi-targeted kinase inhibitor, AT9283, in imatinib-resistant

BCR-ABL positive leukemic cells. Blood 116(12):2089-95. 3. Takeuchi M et al. (2010) Glyoxalase-I induction during hypoxia adaptation in Bcr-Abl positive

leukaemic cells. Cell Death Diff 17:1211-1220. 4. Ashihara E et al. (2010) Future Prospect of RNA interference for cancer therapies. Curr Drug

Targets. 11(3): 345-360, 2010. 5. Ashihara E et al. (2009) Beta-catenin siRNA successfully suppressed progression of multiple

myeloma in a mouse model. Clin Cancer Res, 15:2731-2738. 6. Yokota A et al (2007) INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses

the growth of Ph+ leukemia cells in the central nervous system and cyclosporine A augments its in vivo activity. Blood, 109:306-314

7. Hirai H et al(2006) C/EBPbeta is required for emergency granulopoiesis. Nat Immunol. 7:732-739.

❶ Cell processing for cultured mesenchymal stem cells at CCMT

❷ Novel method using s u r f a c e p l a s m o n resonance to detect anti-A/B antibodies

❸ News release of novel multi-kinase inhibitor for CML

❹ PLK-1 siRNA inhibits progression of liver metastas is in lung cancers

❺ g a m m a d e l t a T cells (small) attack malignant cells (large)

❻ Co l leagues o f the department

Transfusion Medicine and Cell TherapyProfessor : Taira Maekawa Senior Lecturer : Hideyo Hirai Assistant Professor : Yasuo Miura TEL : +81-75-751-3628 +81-75-751-3630 FAX : +81-75-751-3631 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~dtm/

index.html

Transfusion Medicine and Cell Therapy

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- Clinical Medicine (Core Departments)


The Department of Diagnostic Pathology was established in 1980, and has long been recognized as a branch laboratory of investigative pathology and clinical pathology. Diagnostic pathology is a clinical application of proteomics and cellular pathology, contributing to determination of treatment strategy and evaluation of effects of treatment. In accordance with reorganization of the departments of investigative pathology, our department is now responsible for all autopsies and education of systemic pathology for undergraduate students as well as examination and interpretation of surgical specimens and cytopathological specimens in Kyoto University.

Hironori HagaProfessor

Research and EducationMembers of the department are experts in surgical pathology of several organs and some specific diseases. They pursue individual research projects in close cooperation with clinicians and other biomedical researchers. Most of our researches are clinically oriented, and our goal is to provide accurate and scientific diagnosis based on histology and cytology.Current clinical researches include 1) analysis of allograft rejection and other complications after organ transplantation, 2) diagnosis of rare cervical cancers, 3) study on IgG4-related systemic diseases. Other current and previous study included analysis of duodenal cancer, lung cancer, bone tumors, and so on. More basic themes are 1) elucidation of JAK2/STAT5 pathway in development of hematologic malignancies, 2) chimerism and senescence of the liver allograft, and 3) treatment of mast cell disorders. In addition to these studies initiated by pathology members, we are involved in several projects lead by clinicians. Education for graduate students is combination of research and advanced training for diagnostic pathology. Subspecialty training for surgical pathology or cytopathology is encouraged in combination with basic investigative research and /o r t r ad i t i ona l pa tho logy s tudy us ing immunohistochemistry and in situ hybridization. Complete in-house digital pathology database and image analysis using virtual microcopy are also available.

Recent Publications1. Tsuruyama T, Nakai T, Hiratsuka T, Jin G, Nakamura T, Yoshikawa K. In vitro HIV-1 selective

integration into the target sequence and decoy-effect of the modified sequence. PLoS One. 2010;5:e13841.

2. Miyagawa-Hayashino A, Egawa H, Yorifuji T, Hasegawa M, Haga H, Tsuruyama T, Wen MC, Sumazaki R, Manabe T, Uemoto S. Allograft steatohepatitis in progressive familial intrahepatic cholestasis type 1 after living donor liver transplantation. Liver Transpl. 2009;15:610-8.

3. Mikami Y, Kiyokawa T, Sasajima Y, Teramoto N, Wakasa T, Wakasa K, Hata S. Reappraisal of synchronous and multifocal mucinous lesions of the female genital tract: a close association with gastric metaplasia. Histopathology. 2009;54:184-91.

4. Fujimoto M, Haga H, Okamoto M, Obara E, Ishihara M, Mizuta N, Nishimura K, Manabe T. EBV-associated diffuse large B-cell lymphoma arising in the chest wall with surgical mesh implant. Pathol Int. 2008;58:668-71.

5. Yamashita K, Haga H, Kobashi Y, Miyagawa-Hayashino A, Yoshizawa A, Manabe T. Lung involvement in IgG4-related lymphoplasmacytic vasculitis and interstitial fibrosis: report of 3 cases and review of the literature. Am J Surg Pathol. 2008;32:1620-6.

❶ Endothelial chimerism. Original donor endothelium (green) mixed with recipient-derived endothe l ia l ce l l s (b rown) reflecting portal fibrosis and neovessel formation.

❷ C4d-positive chronic rejection after liver transplantation.

❸ IgG4-related lung disease showing vasculitis with IgG4-positive plasma cells.

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Diagnostic PathologyProfessor : Hironori Haga Associate Professor : Yoshiki Mikami, Sachiko Minamiguchi Senior Lecturer : Aya Miyagawa-Hayashino Assistant Professor : Shinji Sumiyoshi TEL : +81-75-751-3488 FAX : +81-75-751-3499 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Diagnostic Pathology

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- Clinical Medicine (Core Departments) - Laboratory of Diagnostic Pathology


Medical informatics is an academic discipline seeking new informatics knowledge and technology that supports medical effectiveness and efficacy.

Medical informatics is growing academic discipline that approaches any academic topics of medicine including basic, clinical and community medicine and topics across their boundaries via technology and knowledge of information science. We are expecting for prospective colleague with full of curiosity, concentration, and, most of all, flexibility to enjoy any academic activities.

Hiroyuki Yoshihara, M.D., Ph.D.Professor

Research and Education1) Planning and designing toward the community healthcare alliance. (fig.1)According the arrival of aging society and new medical technology, total health care expenditure is increasing rapidly in these days. These change result in the rationing of total health care expenditure in national budget. They also result in increasing social pressure toward quality healthcare and efficacy. Such change of environment requires alliance in community to provide appropriate healthcare services without wasting resources. Medical informatics division, collaborating with Kyoto-fu Medical Association, healthcare organizations in the Kyoto Prefecture, Government of Kyoto Prefecture and Kyoto city etc., is planning and designing toward the establishment of community healthcare alliance consortium “MAIKO-net”.

2) Research and Development of Tele-health environment (fig.2)Medical Informatics division is developing an integrated information assistance environment “Surgical Cockpit System” that aim at robotic tele-healthcare in future and its technological infrastructure including application level integrated QoS controlled communication technology.

3) Research and Development of Surgery Simulator (fig.3)To meet the controversies to training high-tech medicine and requirement toward patient safety, innovative educational method to train highly technical surgical operation combining conventional educational method that is conducted on the job training and new information technology is required. Medical informatics division, applying Virtual Reality technology, developed Surgery Simulator that enables surgeons to train the surgical operations under the vision and sense of touch as if the computer generated virtual patient is real.

4) Knowledge Extraction from Practical Data in Medicine (fig.4) We think that the widespread use of Electronic Medical Records (EMRs) gives vast reusable knowledge. However, the study of knowledge extraction from EMR data is on a learning curve to use it as evidence. If we extract reusable knowledge of medicine, it is necessary to benefit from knowledge processing, cognitive science and natural language processing, in addition to medical knowledge. We study medical extraction knowledge from various practical data of hospitals, World Wide Web, medical text and so on.

Recent Publications1. Yoshiaki Nakagawa, Tadamasa Takemura, Hiroyuki Yoshihara and Yoshinobu Nakagawa: A New

Accounting System for Financial Balance Based on Personnel Cost after the Introduction of a DPC/DRG System,Journal of Medical Systems; (Online): ,2009

2. Kuroda Y, Takemura T, Kume N, Okamoto K, Hori K, Nakao M, Kuroda T, Yoshihara H: Semi-automatic development of optimized surgical simulator with surgical manuals., Stud Health Technol Inform.; 125: 250-255, 2007

3. Naoto Kume, Kazuya Okamoto, Takashi Tsukasa, and Hiroyuki Yoshihara: VR-Based Self Brain Surgery Game System by Deformable Volumetric Image Visualization, Virtual Reality, HCII 2007, LNCS 4563; : 670 672, 2007

4. Tadamasa Takemura1, Kazuya Okamoto, Hyogyong Kim, Masahiro Hirose, Tomohiro Kuroda, and Hiroyuki Yoshihara: Context-Based Loose Information Structure for Medical Free Text Document, Human Interface,Part I, HCII 2007, LNCS 4557; : 544 548, 2007

5. Tomohiro Kuroda, Kazuya Okamoto, Ryo Kitauchi, Tadamasa Takemura, Naoki Ohboshi, and Hiroyuki Yoshihara: Finding Origin Points for New Coordinate System Suitable for Sign Animation, Digital Human Modeling, HCII 2007; : 415 422, 2007

❶ Data Centers for accumulating c l i n i c a l i n f o r m a t i o n a r e established in each region. Using these centers, clinical information is shared by clinics and hospitals. Every patient also can refer his/her data.

❷ Surgical Cockpit System (Tele-Medicine)

❸ Virtual Reality based surgical planning and training simmulater

❹ Radiological document retrieval s y s t e m u s i n g a n n o t a t i o n information of schema.

Medical InformaticsProfessor : Hiroyuki Yoshihara Associate Professor : Tomohiro Kuroda Senior Lecturer : Tadamasa Takemura Assistant Professor : Naoto Kume Program-Specific Assistant Professor : Kazuya Okamoto TEL : +81-75-751-3646 FAX : +81-75-751-3076 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/~mi/

Medical Informatics

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- Clinical Medicine (Core Departments) - Medical Informatics


The aim of our laboratory is to establish the scientific bases of appropriate drug usage and pharmaceutical practice for efficient and reliable pharmacotherapy. The efficacy and safety of drugs are closely related to their pharmacokinetics and pharmacodynamics. Therefore, to clarify the pharmacokinetics in human, we have systematically developed the research from drug transport analyses based on the molecular levels to the clinical pharmacokinetics. To settle the problem found in the pharmacotherapy, we attempt to feedback the achievements of basic research (Bench) to clinical practice (Bedside) (Figure 1).

Research and EducationThe pharmacokinetics for various drugs consist of four kinds of processes such as absorption, distribution, metabolism and excretion, and are regulated by various factors including drug transporters. In our laboratory, research projects have been carried out to determine optimal drug therapies in view of pharmacokinetics, having with the theme “laboratory and clinical studies of the pharmacokinetics, effectiveness and toxicity of drugs”. For examples, we have performed functional and molecular characterization of drug transporters expressed in the intestine, kidney and liver, and the establishment of personalized medicine based on the molecular information of drug transporters. Especially, the research on the renal drug excretion has been carried out over 25 years with leading outcomes in this field: i.e., clarification of the transport mechanisms, cDNA cloning of drug transporters, and elucidation of gene regulatory mechanisms for drug transporters and so on. Furthermore, we have expanded research projects to analyze genetic polymorphisms for clinical practice or transcriptional regulatory mechanism of drug transporters, and to identify and analyze H+/organic antiporter in renal proximal tubules and riboflavin transporter.We contribute to personalized medicine of immunosuppressant tacrolimus in the living donor liver transplantation (LDLT). It was demonstrated that the intra- and interindividual variability of tacrolimus pharmacokinetics in allograft recipients is related to the intestinal expression level of MDR1 (ABCB1), an active efflux pump located on the intestinal brush-border membranes, and that the intestinal expression level of MDR1 is a part of prognostic factor for acute cellular rejection and mortality as well as a pharmacokinetic factor in recipients of LDLT (Figure 2). In addition, we establish genome-based population pharmacokinetic model requiring additional CYP3A5 polymorphism and MDR1 mRNA level for individualizing the dosage regimen of tacrolimus in de novo pediatric LDLT recipients. The information is utilized for the determination of the initial dosage regimen for LDLT recipients.Recently, we investigate the personalized medicine of anticancer drugs. To improve safety and efficiency of chemotherapy, we attempt to identify the factors affecting inter-individual variations of pharmacokinetics or adverse effects of anticancer drugs. The graduate students of Medicine and Pharmaceutical Sciences play pivotal roles for laboratory research, and all members have been tackling with difficult scientific problems from various angles, collaborating with pharmacists in Kyoto University Hospital.

Recent Publications1. Yonezawa, A., Inui, K.: Organic cation transporter OCT/SLC22A and H+/organic cation antiporter

MATE/SLC47A are key molecules for nephrotoxicity of platinum agents. Biochem Pharmacol., 81(5):563-8. (2011)

2. Toyama, K., Yonezawa, A., Tsuda, M., Masuda, S., Yano, I., Terada, T., Osawa R, Katsura T, Hosokawa M, Fujimoto S, Inagaki N, Inui K.: Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients., Pharmacogenet Genomics., 20(2):135-8. (2010)

3. Terada, T., and Inui, K.: Physiological and pharmacokinetic roles of H+/organic cation antiporters (MATE/SLC47A). Biochem. Pharmacol., 75(9):1689-1696. (2008)

4. Masuda, S., and Inui, K.: An up-date review on individualized dosage adjustment of calcineurin inhibitors in organ transplant patients. Pharmacol. Ther., 112(1):184-198. (2006) [review]

5. Fukudo, M., Yano, I., Masuda, S., Goto, M., Uesugi, M., Katsura, T., Ogura, Y., Oike, F., Takada, Y., Egawa, H., Uemoto, S., Inui, K.: Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients. Clin. Pharmacol. Ther., 80(4):331-345. (2006)

PharmacyAssociate Professor : Toshiya Katsura, Ph.D. Senior Lecturer : Satohiro Masuda, Ph.D. Assistant Professor : Hideyuki Motohashi, Ph.D., Masahide Fukudo, Ph.D., Atsushi Yonezawa, Ph.D. TEL : +81-75-751-3577 FAX : +81-75-751-4207 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Pharmacy



To improve outcome of treatment or prevention from incurable diseases by creation and development of novel medical treatments and diagnoses is one of the big missions given to the Kyoto University Graduate School of Medicine and to Kyoto University Hospital. For this purpose, Kyoto University Hospital took a new strategy to convert the findings of basic medicine and biology efficiently into novel clinical diagnosis and treatment by establishing a center, named Translational Research Center, to promote such translational and synthetic research. Department of Experimental Therapeutics is for research to discover new drugs and to develop novel methods for diagnosis and treatment. This department has two units, Fixed and Invited Research Project Units. Fixed Research Project Unit, post-genome project, is to develop novel drugs and methods for clinical diagnosis by analyzing human genome information, gene structure and expression. Akira Shimizu, M.D., Ph.D.

Professor

Research and EducationOn order to collect research seeds in nation-wide scale, research proposals suitable for translation termed 3-5 years were invited and selected.Collaborating with other Centers and Institutes of Graduate School of Medicine, Fixed Project unit hosts and supports the research by the Invited Research Project Unit.Our major subject of basic research is to analyze molecular mechanisms underlying higher order functions such as immunity. Active molecular mechanisms appear to suppress IgE class switch recombination (CSR), thereby preventing serious complications during the normal course of the immune response. Analyzing Id2-deficient mice, we found that the switching efficiency of IgE is enhanced in Id2-deficient B cells. Because of the lack of the Id2 gene, increased active E2A and Pax5 proteins bind to the epsilon germline promoter and augment the expression of epsilon germline transcript (GLT). As a consequence, Id2-deficient B cells undergo CSR to IgE at a much higher frequency than wild-type B cells. On the other hand, TGF-Beta1 is known to inhibit CSR to IgE. We also found that Id2 acts as an effector molecule involved in TGF- Beta1 signaling in activated B cells. TGF- Beta1 induces Id2 expression and inhibits IgE CSR. In summary, the TGF- Beta1-Id2 pathway is required to keep the IgE concentration low in the serum. Thus, Id2 might act as a afeguard molecule to prevent harmful effects during the Th2-type immune reaction. Furthermore, it found out that balance of transcription factors including activators such as E2A and Pax5, and inhibitors like Id2 is crucial for activation process and function of lymphocyte. These knowledge are important to understand control mechanisms of lymphocyte activation, and application of these results to the development of a novel treatment of allergy and of a novel method to regulate immune reaction seems to be promising. In addition to these, research on the molecule mechanism for the polarity formation of lymphocytes and the micro-environment formation at the place of immunoreaction is also ongoing.

Recent Publications1. Essential role of Id2 in negative regulation of IgE class switching. Sugai, M., Gonda, H., Kusunoki,

T., Katakai, T., Yokota, Y. and Shimizu, A. Nature Immunol. 4, 25-30 (2003). 2. The balance between Pax5 and Id2 activities is the key to AID gene expression. Gonda, H., Sugai,

M., Nambu, Y., Katakai, T., Agata, Y., Mori, K. J., Yokota Y. and Shimizu, A. J. Exp. Med. 198, 1427-1437 (2003).

3. Tanscription-coupled events associating with immunoglobulin switch region chromatin. Nambu, Y., Sugai, M., Gonda, H., Lee, C.-G., Katakai, T., Agata, Y., Yokota, Y. and Shimizu, A. Science 302, 2137-2140 (2003).

4. Lymph node fibroblastic reticular cells construct the stromal reticulum via contact with lymphocytes. Katakai, T., Hara, T., Sugai, M., Gonda, H. and Shimizu, A. J. Exp. Med. 200, 783-795 (2004).

5. Spontaneous large-scale lymphoid neogenesis and balanced autoimmunity versus tolerance in the stomach of H+/K+-ATPase-reactive TCR transgenic mouse. Katakai, T., Nomura, T., Gonda, H., Sugai, M., Agata, Y., Nishio, A., Masuda, T., Sakaguchi, S. and Shimizu, A. J. Immunol. 177, 7858-7867 (2006).

❶ Id2 deficient mouse s h o w s h y p e r - I g E phenotype.

Frozen sect ions of m i c e i m m u n i z e d by sheep red blood cel ls are observed under f luorescence m i c r o s c o p e . B lymphocytes, IgEs, and germinal center c e l l s a r e s t a i n e d blue, red and green respectively. Most of B lymphocytes of Id2 deficient mouse (right side) passively attach IgE via low aff in i ty receptors reflecting a high IgE concentration in the serum, and cells after IgE CSR (atrined by all the three clolrs) are seen in some of the germinal centers of Id2 deficient mouse.

❷ Model for the egulation o f I g E g e r m l i n e transcription and AID gene expression by E2A, Pax5 and Id2.

Experimental Therapeutics (Fixed Project) Translational Research CenterProfessor : Akira Shimizu Senior Lecturer : Manabu Sugai Assistant Professor : Tatsuya Ito Lecturer (Special Appointment) : Takafumi Ikeda Assistant Professor (Special Appointment) : Kayoko Endo TEL : +81-75-751-4749 FAX : +81-75-751-4905 e-mail : [email protected]

Experimental Therapeutics Translational Research Center

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Clinical trials are defined as intervention studies on human beings that designed to test the hypothesis for diagnostic techniques, treatments, and disease preventions. Any novel medical technologies should be evaluated the efficacy and safety by clinical trials. Our department is the first research branch in Japan to study and educate on clinical trial design, management, statistical analysis, and assessment, which covers from the development of new treatments to establishing of standard therapy.

Research and EducationOur department aims at “to improve treatment outcomes for intractable diseases” and assists in running investigator-sponsored clinical studies (http://www.kutrc.org). At the study planning and protocol development phase, we objectively assess ethical and scientific appropriateness, and feasibility of study. At the implementation phase, we carry out the data management, monitoring, and statistical analysis that is fundamental to the quality control of study, independently with the sponsor and the investigators. The staff members consist of medical doctors, biostatisticians, data managers, monitors, IT specialists, data analysts. For the projects in Translational Research Center of Kyoto University Hospital, we support protocol developments as members of protocol committee, and conduct the data management including CRF (case report forms) designing, database designing, patient enrollment and allocation, data entry and data review. We also perform the monitoring including SDV (source data verification) and safety monitoring, and the statistical analysis including study designing, randomization and data analysis. Since to know state-of-the-art for treatment outcomes is most important for designing clinical trials, we carry out lots of outcomes research in collaboration with medical departments.

Recent Publications1. Teramukai S, Kitano T, Kishida Y, et al. Pretreatment neutrophil count as an independent

prognostic factor in advanced non-small-cell lung cancer: An analysis of Japan Multinational Trial Organisation LC00-03. Eur J Cancer 2009;45: 1950-1958.

2. Kishida Y, Kawahara M, Teramukai S, et al. Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small-cell lung cancer: Results from Japan Multinational Trial Organization LC00-03. Br J Cancer 2009;101: 1537-1542.

3. Tada H, Teramukai S, Fukushima M, et al. Risk factors for lower limb lymphedema after lymph node dissection in patients with ovarian and uterine carcinoma. BMC Cancer 2009;9: 47.

4. Zhou B, Teramukai S, Yoshimura K, et al. Validity of cerebrospinal fluid biomarkers as endpoints in early-phase clinical trials for Alzheimer’s disease. J Alzheimers Dis 2009;18: 89-102.

5. Nishizawa S, Kojima S, Teramukai S, et al. Prospective evaluation of whole-body cancer screening with multiple modalities including [18F]fluorodeoxyglucose positron emission tomography in a healthy population: A preliminary report. J Clin Oncol 2009;27: 1767-1773.

6. Zohar S, Teramukai S, Zhou Y. Bayesian design and conduct of phase II single-arm clinical trials with binary outcomes: A tutorial. Contemp Clin Trials 2008;29: 608-616.

7. Egawa H, Teramukai S, Haga H, et al. Present status of ABO-incompatible living donor liver transplantation in Japan. Hepatology 2008;47: 143-152.

8. Teramukai S, Ochiai K, Tada H, Fukushima M. PIEPOC: A new prognostic index for advanced epithelial ovarian cancer – Japan Multinational Trial Organization OC01-01. J Clin Oncol 2007;25: 3302-3306.

9. Teramukai S, Nishiyama H, Matsui Y, Ogawa O, Fukushima M. Evaluation for surrogacy of end points by using data from observational studies: Tumor downstaging for evaluating neoadjuvant chemotherapy in invasive bladder cancer. Clin Cancer Res 2006;12: 139-143.

❶ Software for Protocol Development (Study Designer)

Clinical Trial Design and Management Translational Research CenterAssociate Professor : Satoshi Teramukai Assistant Professor : Harue Tada, Miyuki Niimi, Shiro Tanaka, Kenichi Yoshimura TEL : +81-75-751-3858 FAX : +81-75-751-4732 e-mail : [email protected] URL : http://www.kutrc.org

Clinical Trial Design and Management Translational Research Center

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Translational research center was established to translate potential therapies into clinical outcomes. A new paradigm is sought to obviate many of the problems associated with translation of basic science findings. The Department of Clinical Innovative Medicine was founded in 2002 for this purpose to organize and head a medical team that could pursue highly advanced therapies safely and relevantly. We have collaborated with Department of Experimental Therapeutics in order particularly to promote the preclinical studies for clinical application. We are also eager to guarantee scientific and ethical relevance of the clinical trials and have co-operated with the Department of Clinical Design and Management. Our physicians, research nurses, and research pharmacists are not only leading multidisciplinary team but also are expert at OPC and wards, getting informed consent from the patients, and caring after the patients who have left the hospital. Based on these achievements, we wish to propose the new paradigm to enable rational translation of important basic science findings into clinical use.

Masayuki Yokode, M.D., Ph.D.Professor

Research and EducationWe focus our research target on creation of a new clinical paradigm of translational research that emphasizes efficacy and clinically relevant outcomes. We furthermore wish to create a system for rigorous preclinical testing of promising potential therapies with clinical trial approaches so that preclinical research would be assessed under standardized criteria. We are eager to educate graduate students interested in clinical studies who wish to learn while they are working for the patients. Also, scientific basis of the trials, i.e., blinded, randomized, multicentered, and adequately powered studies using standardized methods will be taught. We do call for the young promising students who wish to study with us to lead the clinical studies of the nation.

Recent Publications1. Hatta T, Murayama T, Narita K, Sumi E, Yokode M Trend Analysis of Informed Consent Research

in Clinical Trials: Comprehensive Retrieval via Electronic Databases. Jpn J ClinPharmacol Therapeutics 2011; 42: 21-25.

2. Minami M, Matsumoto S, Horiuchi H. Cardiovascular side-effects of modern cancer therapy. Circ J 2010; 74:1779-1786.

3. Nakase H, Fujiyama Y, Oshitani N, Oga T, Nonomura K, Matsuoka T, Esaki Y, Murayama T, Teramukai S, Chiba T, Narumiya S. Effect of EP4 agonist (ONO-4819CD) for patients with mild to moderate ulcerative colitis refractory to 5-aminosalicylates: A randomized phase II, placebo-controlled trial. Inflamm Bowel Dis 2010; 16: 731-733.

4. Horie T, Ono K, Horiguchi M, Nishi H, Nakamura T, Nagao K, Kinoshita M, Kuwabara Y, Marusawa H, Iwanaga Y, Hasegawa K, Yokode M, Kimura T, Kita T. MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. ProcNatlAcadSci U S A. 2010; 107:17321-17326.

5. Tamura Y, Sugimoto M, Murayama T, Minami M, Nishikaze Y, Ariyasu H, Akamizu T, Kita T, Yokode M, Arai H. C-C Chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice. J ArteriosclerThromb 2010; 17: 219-228.

6. Sumi E, Murayama T, Yokode M. A survey of attitudes toward clinical research among physicians at Kyoto University Hospital. BMC Med Edu 2009; 9: 75.

❶ Paradigm of Translational Research ❷ informed consent ❸ members

Clinical Innovative Medicine Translational Research CenterProfessor : Masayuki Yokode Senior Lecturer : Toshinori Murayama Assistant Professor : Eriko Sumi, Manabu Minami, Toshiko Ihara, Noboru Ashida, Takahiro Horie TEL : +81-75-751-4743 FAX : +81-75-761-6816 e-mail : [email protected]

Clinical Innovative Medicine Translational Research Center

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We are engaged in the research works on the human brain function using non-invasive technique, such as MRI, PET, MEG, TMS and so on. Our main purpose is directed to disclose the functional localization and connectivity of the human brain, and research the physiological mechanisms of the disorders in the CNS. We think that it is the most important thing to explore the brain function from the various aspects using available imaging or physiological apparatus.

Hidenao Fukuyama, M.D., Ph.D.Professor

Research and EducationRecent advances on the molecular imaging stimulate us to do the work related this field. The basic concept is to expand the functional significance of the gene or subsequent protein products in vivo. The neuroscience itself is dedicated to find out the functions of the human brain, but we have to explore the animal brain for its final goal, because human brain is specific to human being and also we cannot do any invasive technique to the human brain except for the special occasions. It was reported that beta-amyloid is visualized using PET. In the near future, we can image the various kinds of proteins or other substances without invasive exploratory procedures. This is the dream and final direction of the neuroscience in one aspect.Another is the research to help the disadvantaged brain with the knowledge of the normal brain functions. Rehabilitation is regarded as one of the regeneration medicine. HBRC is one of the departments that concern with the neuroscience and clinical neurology. Therefore, we have also keen interest in this aspect, and devote the efforts to make help for disadvantaged people.We will welcome every person to join us and do the research activities, who have the similar interests.

Recent Publications1. Badry, R., Mima, T., Aso, T., Nakatsuka, M., Abe, M., Fathi, D., Foly, N., Nagiub, H., Nagamine,

T. and Fukuyama, H. (2009). "Suppression of human cortico-motoneuronal excitability during the Stop-signal task." Clin Neurophysiol 120(9): 1717-23.

2. Aso, T., Urayama, S., Poupon, C., Sawamoto, N., Fukuyama, H. and Le Bihan, D. (2009). "An intrinsic diffusion response function for analyzing diffusion functional MRI time series." Neuroimage 47(4): 1487-95.

3. Kohno, S., Sawamoto, N., Urayama, S., Aso, T., Aso, K., Seiyama, A., Fukuyama, H. and Le Bihan, D. (2009). "Water-diffusion slowdown in the human visual cortex on visual stimulation precedes vascular responses." J Cereb Blood Flow Metab 29(6): 1197-207.

4. Takaya, S., Mikuni, N., Mitsueda, T., Satow, T., Taki, J., Kinoshita, M., Miyamoto, S., Hashimoto, N., Ikeda, A. and Fukuyama, H. (2009). "Improved cerebral function in mesial temporal lobe epilepsy after subtemporal amygdalohippocampectomy." Brain 132(Pt 1): 185-94.

5. Aso, K., Hanakawa, T., Aso, T. and Fukuyama, H. "Cerebro-cerebellar Interactions Underlying Temporal Information Processing." J Cogn Neurosci.

❶ 306 channel whole-head MEG measures neuronal electrical ac t i v i t y a t h i gh t empo ra l resolution.

❷ 3 tesla MRI scanner visualizes brain structure and function at high spatial resolution.

❸ Trac tog raphy ana l ys i s o f diffusion MRI data identifies connectivity among brain areas.

❹ Member of the laboratory.

Brain Pathophysiology / Functional Brain ImagingHuman Brain Research CenterProfessor : Hidenao Fukuyama, Denis Le Bihan Associate Professor : Hiroshi Yamauchi, Tatsuya Mima Assistant Professor : Nobukatsu Sawamoto, Shinichi Urayama TEL : +81-75-751-3695 FAX : +81-75-751-3202 e-mail : [email protected] URL : http://hbrc.kuhp.kyoto-u.ac.jp/

Brain Pathophysiology / Functional Brain Imaging Human Brain Research Center

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- Clinical Medicine (Core Departments) - Human Brain Research Center


We research the mechanisms of functional deterioration of organs, tissues, and cells during preservation. Further, we develop novel methods and techniques to effectively preserve organs, tissues, and cells. Kyoto University has developed the original organ preservation solution named ET-Kyoto solution, and proven its protective effect in various organ preservation. Based on the knowledge, our department was established in August 2006 to investigate wide range of clinics-oriented themes.

Research and EducationTransplantation of various organs including the lung, heart, liver, kidney, islets, and small intestine has been established as the solo therapeutic option for end-stage organ dysfunction. Additionally, various relating therapies including bone marrow transplantation for leukemia, immuno-cell therapies for cancer, and replantation of amputated digits are emerging. However, the quality and quantity of organs, tissues and cells transplanted after preservation is not yet satisfactory. Therefore, elucidating the mechanisms of functional deterioration after preservation and improving the quality of organs, tissues, and cells would directly benefit patients for those advanced therapies. Reliable methods of preservation would enable the use of marginal donors and alleviate the shortage of donor organs. Good function of preserved organs, tissues, and cells would lessen complications after therapies and contribute to the medical economics. Further, knowledge on organ, tissue and cell preservation would also provide better results in regenerative medicine. Our department would like to collaborate many researches, and perform basic as well as pre-clinical studies.

Recent Publications1. Zhao X, Koshiba T, Nakamura T, Tsuruyama T, Li Y, Bando T, Wada H, Tanaka K. ET-Kyoto

Solution plus Dibutyryl Cyclic Adenosine Monophosphate is Superior to University of Wisconsin Solution in Rat Liver Preservation. Cell Transplantation, in press.

2. Chen F, Kondo N, Sonobe M, Fujinaga T, Wada H, Bando T. Expression of endothelial specific adhesion molecules after cardiac arrest. Int Cardiovasc Thorac Surg 2008 Feb 15; [Epub ahead of print].

3. Fujinaga T, Nakamura T, Fukuse T, Chen F, Zhang J, Ueda S, Hamakawa H, Omasa M, Sakai H, Hanaoka N, Wada H, Bando T. Isoflurane inhalation after circulatory arrest protects against warm ischemia reperfusion injury of the lungs. Transplantation 2006; 82: 1168-72.

4. Chen F, Nakamura T, Fujinaga T, Zhang J, Hamakawa H, Omasa M, Sakai H, Hanaoka N, Bando T, Wada H, Fukuse T. Protective effect of a nebulized Beta2-adrenoreceptor agonist in warm ischemic–reperfused rat lungs. Ann Thorac Surg 2006; 82: 465-71.

5. Noguchi H, Ueda M, Nakai Y, Iwanaga Y, Okitsu T, Nagata H, Yonekawa Y, Kobaya N, Nakamura T, Wada H, Matsumoto S. Modified two-layer preservation method (M-Kyoto/PFC) improves islet yields in islet isolation. Am J Transplant 2006; 6:496-504.

❶ R a t l u n g ex v i vo p e r f u s i o n model newly developed by our department (Figure 1).

❷ The device enabled us to measure the physiological data on time in various conditions Harvested rat heart-lung block (Figure 2, Ref. 4 and 5)

❸ Clinical application of our organ preservation solution, ET-Kyoto solut ion (Figure 3). ET-Kyoto solution showed both a splendid lung funct ion and h is to log ic findings even in the setting of more than 10 hours of ischemia in a clinical lung transplantation. This solution has been used not only lung transplantation but also many other transplantations, such as kidney, liver, and islet cell.

❹ Large animal ex vivo perfusion model, currently being developed by our department (Figure 4). To investigate organ function in a setting closer to clinical situation, we are currently preparing and developing a large animal ex vivo perfusion model.

Organ Preservation TechnologyAssociate Professor : Toru Bando, MD, PhD Assistant Professor : Takuji Fujinaga, MD, PhD, Fengshi Chen, MD, PhD, Xiangdong Zhao, MD, PhD TEL : +81-75-751-3837 FAX : +81-75-751-4647 e-mail : [email protected]

Organ Preservation Technology Contributed Chairs

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- Clinical Medicine (Core Departments) - Department of Organ Preservation Technology


The Department of Respiratory Care and Sleep Control Medicine is a new department which was started on April 1, 2008. The purpose of the department is to investigate the blood gas levels which are essential to life. One of our key research areas is hypoxemia with or without hypercapnia, and research in this department includes 1) refractory acute respiratory failure, including acute respiratory distress syndrome, 2) sleep disordered breathing such as sleep apnea, which has a significant effect on life-style related diseases such as cardiovascular diseases, and 3) sleep associated symptoms such as excessive daytime sleepiness. From translational research, we hope to develop a new therapy for respiratory failure and sleep disordered breathing.

Kazuo Chin (Hwa Boo Jin) M.D., Ph.D.Professor

Research and EducationBased on pulmonary physiology such as the regulation of breathing while awake and asleep, gas exchange, and lung mechanics, the purpose of the Department of Respiratory Care and Sleep Control Medicine is to investigate blood gas levels which are essential life. From translational research, we hope to develop new therapies for respiratory failure and sleep disordered breathing. In addition, this department teaches how to manage respiratory failure, sleep disordered breathing and excessive daytime sleepiness. For example, we teach how to manage acute or chronic respiratory failure by using oxygen, noninvasive ventilation (NIV) such as continuous positive airway pressure (CPAP), noninvasive positive pressure ventilation (NPPV) and adapted servo ventilation (ASV), and intermittent positive pressure ventilation (IPPV) via tracheostomy or intubation (Figure 1). Recently, it has been shown that intermittent and/or sustained hypoxia (IH and/or SH), which are induced by sleep disordered breathing such as sleep apnea, have significant effects on morbidity and mortality through transcriptional factors such as NFkappaB and hypoxia inducible factor-1 (HIF-1). We will research the effects of IH and SH using molecular biology and new techniques (Figure 2). We’ll also investigate the pathophysiological effects of IH and SH on humans and animals by using noninvasive methods such as polysomnography. Through such research we will determine the effects of IH and SH on refractory respiratory failure, metabolic syndrome (Figure 3), and life-style related diseases such as cardiovascular diseases and diabetes mellitus. In the near future, we will want to make personalized medicine for sleep disturbance including sleep disordered breathing. We also hope to develop new machines and drugs which manage several refractory respiratory failures, including acute respiratory distress syndrome and pulmonary fibrosis (Figure 4).

Recent Publications1. Chin K, Oga T, Takahashi K, Takegami M, Nakayama-Ashida Y, Wakamura T, Sumi K, Nakamura

T, Horita S, Oka Y, Minami I, Fukuhara S, Kadotani H. Associations between obstructive sleep apnea, metabolic syndrome and sleep duration, as measured with an actigraph, in an urban male working population in Japan. Sleep 2010; 33:89-95.

2. Oga T, Matsuoka T, Yao C, Nonomura K, Kitaoka S, Sakata D, Kita Y, Tanizawa K, Taguchi Y, Chin K, Mishima M, Shimizu T, Narumiya S. Prostaglandin F2alpha receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta. Nat Med 2009; 15: 1426- 30.

3. Takahashi K, Chin K, Nakamura H, Morita S, Sumi K, Oga T, Matsumoto H, Niimi A, Fukuhara S, Yodoi J, Mishima M. Plasma thioredoxin, a novel oxidative stress marker, in patients with obstructive sleep apnea before and after nasal continuous positive airway pressure. Antioxidants & Redox Signaling 2008; 10:715-726.

4. Chin K, Nakamura T, Fukuhara S, Takahashi K, Sumi K, Matsumoto H, Niimi A, Mishima M, Nakamura T. Falls in blood pressure in patients with obstructive sleep apnoea after long-term nasal continuous positive airway pressure treatment. Journal of Hypertension 2006; 24;2091-2099

5. Chin K, Uemoto S, Takahashi K, Egawa H, Kasahara M, Fujimoto Y, Sumi K, Mishima M, Sullivan CE, Tanaka K. Noninvasive ventilation for pediatric patients including those under a year undergoing liver transplantation. Liver Transplantation 2005;11:188-195.

❶ Respiratory complications in children following living donor liver transplantation improved by using noninvasive positive pressure ventilation.

❷ A machine which can produce intermittent and sustained hypoxia in several cells.

❸ Abdominal adipose tissue accumulation and serum leptin levels decrease after CPAP treatment

❹ Effects of PGF2alpha on proliferation and collagen production of lung fibroblasts.

Respiratory Care and Sleep Control MedicineProfessor : Kazuo Chin (Hwa Boo Jin) Associate Professor : Tomomasa Tsuboi Senior Lecturer : Toru Oga Assistant Professor : Takefumi Hitomi TEL : +81-75-751-3852 FAX : +81-75-751-3854 e-mail : [email protected]

Respiratory Care and Sleep Control Medicine Contributed Chairs

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- Clinical Medicine (Core Departments) - Department of Respiratory Care and Sleep Control Medicine


Research in the field of clinical oncology aims to advance the treatment of cancer, with a particular focus on chemotherapy, but also supportive care. Translational clinical oncology is a field of study that aims to translate the findings arising from basic research (e.g. in the fields of pharmacology, pharmacogenetics or tumor biology) into clinical oncology practice. The Department of Translational Clinical Oncology was founded in October 2003 to facilitate such translational research. It was also founded with the aim of developing an effective database system to support the implementation of clinical trials, which are essential to providing patients with new drugs for cancer chemotherapy. Based at the Outpatient Oncology Unit of Kyoto University Hospital, the department is also dedicated to developing a database system to support safe and effective chemotherapy for cancer patients.

Research and EducationResearch activities(1) Development of a database system to support practical cancer chemotherapy: We have developed a database system that allows doctors, nurses, pharmacists, and other practitioners to share patient information, and can help identify problems for discussion in clinical conferences.(2) Development of a database system to support clinical trials: We have developed a database system that outputs case report forms by using information from patients’ electronic health records (e.g. adverse events or laboratory data). (3) Clinical study of cancer chemotherapy: Using the above-mentioned clinical trial database system, we have conducted a number of phase II clinical trials such as TS-1 and docetaxel for the treatment of previously treated non-small cell lung cancer, and TS-1 and gemcitabine for the treatment of recurrent or inoperable biliary tract cancers. We have also conducted some outcomes studies, for example of modified FOLFOX6 for the treatment of advanced or recurrent colorectal cancer. (4) Clinical study of supportive care in cancer chemotherapy: We are exploring measures to alleviate the pain associated with gemcitabine infusion, and investigating the risk factors for chemotherapy-induced anemia and oxaliplatin-induced allergic reactions.(5) Pharmacogenetic study in cancer chemotherapy: We are investigating the relationships between genetic polymorphisms and the incidence of adverse events and/or the effectiveness of a treatment. We are currently studying pharmacogenetic factors in TS-1 treatment for gastrointestinal cancer and oxaliplatin-induced sensory neuropathy.

Recent Publications1. Yamamoto K, Matsumoto S, Tada H, Yanagihara K, Teramukai S, Takemura T, Fukushima

M. A data capture system for outcomes studies that integrates with electronic health records: development and potential uses. J Med Syst. 2008;32:423-7.

2. Yanagihara K, Yoshimura K, Niimi M, Yasuda H, Sasaki T, Nishimura T, Ishiguro H, Matsumoto S, Kitano T, Kanai M, Misawa A, Tada H, Teramukai S, Mio T, Fukushima M. Phase II study of S-1 and docetaxel for previously treated patients with locally advanced or metastatic non-small cell lung cancer. Cancer Chemother Pharmacol. 2010 ;66(5):913-8.

3. Kanai M, Yoshioka A, Tanaka S, Nagayama S, Matsumoto S, Nishimura T, Niimi M, Teramukai S, Takahashi R, Mori Y, Kitano T, Ishiguro H, Yanagihara K, Chiba T, Fukushima M, Matsuda F. Associations between glutathione S-transferase pi Ile(105)Val and glyoxylate aminotransferase Pro(11)Leu and Ile(340)Met polymorphisms and early-onset oxaliplatin-induced neuropathy. Cancer Epidemiol. 2010 ;34(2):189-93.

4. Mori Y, Nishimura T, Kitano T, Yoshimura K, Matsumoto S, Kanai M, Hazama M, Ishiguro H, Nagayama S, Yanagihara K, Teramukai S, Chiba T, Sakai Y, Fukushima M. Oxaliplatin-free interval as a risk factor for hypersensitivity reaction among colorectal cancer patients treated with FOLFOX. Oncology. 2010;79:136-43.

5. Kitano T, Tada H, Nishimura T, Teramukai S, Kanai M, Nishimura T, Misawa A, Yoshikawa K, Yasuda H, Ishiguro H, Matsumoto S, Yanagihara K, Fukushima M. Prevalence and incidence of anemia in Japanese cancer patients receiving outpatient chemotherapy. Int J Hematol. 2007;86:37-41.

❶ Comparison of standard clinical database systems and our cancer clinical database system (Cyber Oncology®). Generally, when an attempt is made to use electronic health record (EHR) data for clinical studies, data are obtained directly from the medical records. In contrast, Cyber Oncology® acts as a front-end component of the EHR system.

❷ Architecture of the cancer clinical database system. The system comprises four sub-systems: the Cyber Oncology® cancer clinical database system, the cl inical support system, the daily reports system and the data analysis system.

❸ Phase II study of S-1 and docetaxel for previously treated patients with locally advanced or metastatic non -sma l l ce l l l ung cancer : Kaplan–Meier survival curves demonstrating overall (solid line) and progression-free (dashed line) survival. OS overall survival, PFS progression-free survival

Translational Clinical OncologyProgram-Specific Associate Professor : Kazuhiro Yanagihara Program-Specific Senior Lecturer : Takafumi Nishimura Program-Specific Assistant Professor : Shigemi Matsumoto, Toshiyuki Kitano TEL : +81-75-751-4770 FAX : +81-75-751-4772 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

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Translational Clinical Oncology

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- Clinical Medicine (Core Departments) - Department of Translational Clinical Oncology


Ghrelin is a novel acylated peptide discovered from the stomach in 1999 and exhibits a variety of biological activities including the stimulation of growth hormone release and food intake. We are attempting to apply ghrelin to the treatment of disorders related to appetite and growth hormone secretion.

Takashi Akamizu M.D., Ph.D.Special Appointment Professor

Research and Education1.Basic Research· Pathophysiological role of ghrelin · New physiological function of ghrelin· Regulation of ghrelin secretion/production

2.Clinical Trials· Phase I: finished· Phase II: Two trials finished, One ongoing

3.EducationDrug discovery using peptidesMethodology and systems of translational research

Recent Publications1. Iwakura H, Li Y, Ariyasu H, Hosoda H, Kanamoto N, Bando M, Yamada Go, Hosoda K, Nakao

K, Kangawa K, Akamizu T. Establishment of a novel ghrelin-producing cell line. Endocrinology. 151(6):2940-5, 2010

2. Ariyasu H, Iwakura H, Yamada G, Kanamoto N, Bando M, Kohno K, Sato T, Kojima M, Nakao K, Kangawa K, Akamizu T. A post-weaning reduction in circulating ghrelin temporarily alters GH responsiveness to GHRH in male mice, but does not affect somatic growth. Endocrinology. 151(4):1743-50, 2010

3. Yamada G, Ariyasu H, Iwakura H, Hosoda H, Akamizu T, Nakao K, Kangawa K. Generation of transgenic mice overexpressing a ghrelin analog. Endocrinology. 151(12):5935-40, 2010

4. Iwakura H, Ariyasu H, Li Y, Kanamoto N, Bando M, Yamada Go, Hosoda H, Hosoda K, Shimatsu A, Nakao K, Kangawa K, Akamizu T: A mouse model of ghrelinoma exhibited activated growth hormone-insulin-like growth factor I axis and glucose intolerance. Am J Physiol Endocrinol Metab. 297(3):E802-11, 2009.

5. Ariyasu H, Iwakura H, Yamada G, Nakao K, Kangawa K, Akamizu T: Efficacy of Ghrelin as a therapeutic approach for age-related physiologic changes. Endocrinology. 149:3722-8, 2008.

❶ Structure of Ghrelin ❷ Function and Clinical applications

of Ghrelin ❸ Lab Personnel

Ghrelin Research ProjectTranslational Research CenterSpecial Appointment Professor : Takashi Akamizu Assistant Professor : Hiroshi Iwakura, Hiroyuki Ariyasu TEL : +81-75-751-4720 FAX : +81-75-751-4731 e-mail : [email protected] URL : http://www.kuhp.kyoto-u.ac.jp/

~ghrelin/

Ghrelin Research Project Translational Research Center

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- Translational Research Center

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On the basis of molecular imaging technique, which is promising for early detection of solid tumors, we aim at development of a new imaging probe for novel clinical diagnosis. Our strategy is to utilize a novel nanocarrier, molecular assembly of poly(L-lactide)-co-polypeptide and named “lactosome”, to be equipped with a signal unit and a targeting unit. Lactosome accumulates passively in tumors. With labeling and entrapment of anti-cancer drugs, “lactosome” is going to be an excellent imaging/delivery system.

Shunsaku Kimura, Ph.D.Professor

Research and Educationi) Cooperation of medicine, engineering, and pharmacology: Cutting-edge medical technology will be achieved by collaborative researches between medicine, engineering, and pharmacology. Clinical application of the technology is prime for our collaboration to develop a novel diagnosis method here for early detection of solid tumors by molecular imaging.ii) Imaging/targeting: Combination of a signal unit, targeting unit, and anti-cancer drugs is realized in the present project by using lactosome, molecular assembly of poly(L-lactide)-co-polypeptide, as nanocarrier. With this conjugation, simultaneous imaging and targeting will be possibly attained.iii) Lactosome: Lactosome has an advantage as nanocarrier because of its high stealth effect. We have succeeded thus in imaging of tiny liver cancer grafted in liver. For further high functionalization of lactosome, we are optimizing the molecular assembly.i v ) C l i n i c a l a p p l i c a t i o n : M e d i c i n a l a n d pharmacological test, pharmacokinetics studies, safety pharmacologic test, and toxicity test are scheduled in the project period of five years. Further, we will prepare the protocol for clinical trial under cooperation of Translational Research Center.

Recent Publications1. H. Tanisaka, S. K. Kondoh, A. Makino, S. Tanaka, M. Hiraoka, S. Kimura, Near-Infrared

Fluorescent Labeled Peptosome for Application to Cancer Imaging, Bioconjugate Chem., 19, 109-117 (2008)

2. K. Kitagawa, T. Morita, S. Kimura, A Helical Molecule That Exhibits Two Length in Response an Applied Potential, Angew. Chem., Int. Ed., 44, 6330-6333 (2005)

3. S. Yasutomi, T. Morita, Y. Imanishi, S. Kimura, A Molecular Photodiode System That Can Switch Photocurrent Direction, Science, 304, 1944-1947 (2004)

4. S. Kimura, Y. Imanishi, Enkephalin-Cell Interactions, Vitamins and Hormones, 59, 133-158 (2000) 5. K.-Y. Nam, M. Hiro, S. Kimura, H. Fujiki, Y. Imanishi, Permeability of a Non-TPA-Type Tumor

Promoter, Okadaic Acid, through Lipid Bilayer membrane, Carcinogenesis, 11, 1171-1174 (1990)

❶ Imaging of liver cancer (HepG2) grafted in liver by using lactosome labeled with NIR fluorescence probe of ICG.

Lactosome ProjectTranslational Research CenterProfessor : Shunsaku Kimura Assistant Professor : Kensuke Kurihara TEL : +81-75-383-2400 FAX : +81-75-383-2401 e-mail : [email protected] URL : http://pixy.polym.kyoto-u.ac.jp/

lactosome.html

Lactosome Project Translational Research Center

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Chromosomal DNA, a carrier of the blue print of life, must be faithfully duplicated and equally delivered to two daughter cells. Cells with extra chromosomes or less chromosomes (aneuploids), which are generated through unequal segregation of chromosomes, are a primary cause of genetic diseases such as Down syndrome. They have a great impact on tumor development/progression as well. We study mechanisms required for equal segregation of chromosomes with yeast and cultured human cells as major research materials.

Tomohiro Matsumoto, Ph.D.Professor

Research and EducationA series of the biochemical reactions necessary for self-duplication of life are orderly programmed in the cell cycle. In particular, most of the reactions, which are initiated once and only once at a specific stage of the cell cycle (such as DNA replication and segregation), are triggered by the completion of the preceding reaction. It is generally accepted that negative feedback loops (so called checkpoints) are responsible for suppression of the onset of a reaction until the completion of the preceding reaction. That sister chromatid separation must follow the completion of attachment of the spindle to all kinetochores is an important rule for equal segregation of chromosomes. The spindle checkpoint, our major research subject, is a surveillance mechanism to regulate cellular apparatus for compliance with this rule. It is a unique negative feedback that converts/amplifies a physical signal sensed by kinetochores (attachment of the spindle and/or tension) and regulates the timing of the sister chromatid separation. Mad2, a signal carrier of this feedback, plays a vital role in the spindle checkpoint. It is specifically localized at unattached kinetochores that are the origin of the checkpoint signal. Mad2 targets CDC20 and inhibits its activity to promote sister chromatid separation. We study Mad2, a central player of the spindle checkpoint, to reveal mechanisms, which regulate the activity of Mad2.

Recent Publications1. Guohong Xia, Xuelian Luo, Toshiyuki Habu, Josep Rizo, Tomohiro Matsumoto, and Hongtao Yu

(2004) Conformation-specific binding of p31comet to Mad2 antagonizes the function of Mad2 in the spindle checkpoint. EMBO J. 23:3133-3143.

2. Luo X., Tang Z., Xia, G., Wassmann K., Matsumoto T., Rizo, J. and Yu H. (2004) The Mad2 spindle checkpoint protein has two distinct natuively folded states. Nat Struct Mol Biol. 11:338-345.

3. Habu, T., Kim, S. H., Weinstein, J., and Matsumoto, T. (2002). Identification of a Mad2-binding protein, Cmt2, and its role in mitosis. EMBO J. 21: 6419-6428.

4. Kim, S. H., Lin, D. P., Matsumoto, S., Kitazono, A. and Matsumoto, T. (1998). Fission yeast Slp1: An effector of the Mad2-dependent spindle checkpoint. Science 279:1045-1047.

❶ Sister chromatid separation at the onset of anaphase. Chromosomes (red) and the spindle (green) were stained with fluorescence.

❷ Distribution of Mad2 at prophase. Nuclear membrane (red), Mad2 (green) and chromosomal DNA (blue) were stained with fluorescence.

❸ Staffs

Radiation System BiologyRadiation Biology CenterProfessor : Tomohiro Matsumoto Assistant Professor : Toshiyuki Habu TEL : +81-75-753-7552 FAX : +81-75-753-7564 e-mail : [email protected] URL : http://www.rbc.kyoto-u.ac.jp/

Radiation System Biology (Laboratory of Genome Maintenance)

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- Radiation Biology Center


The purpose of our research is to clarify the role of chromatin remodeling, which is required for the DNA metabolisms such as transcription, DNA replication, and DNA repair. In particular, we focus on the molecular mechanisms by which histone modifier complexes regulate the histone eviction as chromatin remodeling machinery upon DNA damage induced by ionizing radiation. We use the protein complex purification system in combination with genetic analysis to determine the relationship between histone eviction and DNA damage signaling pathway. Our goal is to understand how histone eviction activates DNA damage signaling pathways and functions as an anti-cancer signaling.

Research and EducationEukaryotic genome is tightly packed into the chromatin, a hierarchically organized complex of DNA, histone and nonhistone proteins. This packing represents a common obstacle for most of the DNA functions. Concerning transcription, covalent modifications of core histone N-termini and ATP-dependent nucleosome remodeling plays a role in regulation of gene expression in the chromatin context. On the other hand, role of these chromatin modifications in other aspects of DNA metabolism, especially DNA repair, remains largely unexplored. We have shown that TIP60 histone acetylase complex involved in DNA repair and apoptosis. However, it remains unknown how TIP60 complex involve in DNA repair. To better understand the mechanism of TIP60 complex in DNA repair, TIP60 complex purifies from chromatin soluble fraction after exposure of ionizing radiation. As a result, the TIP60 complex is associated with chromatin including histone H2AX after DNA damage. Histone H2AX, histone H2A variant, is phosphorylated at the site of DNA double-strand breaks (DSBs). We found that TIP60 acetylates histone H2AX. By acetylating H2AX, TIP60 stimulates i ts ubiquitination by the ubiquitin-conjugating enzyme UBC13. Furthermore, we revealed that the acetylation-dependent ubiquitination by the TIP60-UBC13 complex leads to the eviction of H2AX from damaged chromatin using live cell imaging and UV laser micro-irradiation. Since ubiquitination of H2AX is required for the recruitment of DNA repair and checkpoint proteins at the damage site, TIP60/UBC13-dependent eviction of H2AX may function as a molecular link between DNA damage sensing and chromatin remodeling. We are now investigating the role of the eviction of H2AX upon DNA damage in chromatin remodeling and checkpoint activation.

Recent Publications1. Ikura, T., Ogryzko, V V., Grigoriev, M., Groisman, R., Wang, J., Horikoshi, M., Scully, R., Qin, J.,

Nakatani, Y. Involvement of the TIP60 Histone Acetylase Complex in DNA repair and apoptosis (2000). Cell. 102: 463-473.

2. Fuchs, M., Gerber, J., Drapkin, R., Sif, S., Ikura, T., Ogryzko, V., Lane, WS., Nakatani, Y., Livingston, DM. The p400 complex is an essential E1A transformation target (2001).Cell. 106: 297-307.

3. Ikura, T., Tashiro, S., Kakino, A., Shima, H., Jacob, N., Amunugama, R., Yoder, K., Izumi, S., Kuraoka, I., Tanaka, K., Kimura, H., Ikura, M., Nishikubo, S., Ito, T., Muto, A., Miyagawa, K., Takeda, S., Fishel, R., Igarashi, K., Kamiya, K. DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics (2007). Mol. Cell. Biol. 27: 7028-40.

4. Dohi, Y., Ikura, T., Hoshikawa, Y., Katoh, Y., Ota, K., Nakanome, A., Muto, A., Omura, S., Ohta, T., Ito, A., Yoshida, M., Noda, T., Igarashi, K. Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin (2008). Nat. Struct. Mol. Biol. 15. 1246-54.

❶ Model for the role of TIP60 and UBC13 in DNA damage response. The TIP60 complex is recruited t o t h e d a m a g e d c h r o m a t i n immediately after induction of DSBs and acety lates H2AX. UBC13 is recruited and/or the activity of UBC13 is modulated by T I P 6 0 , fa c i l i t a t e s p o l y -ubiquitination of H2AX, resulting in histone H2AX eviction for the repair of DSBs.

❷ The strategy fro the TIP60 complex purification Nuclear extracts were prepared from HeLa cells stably expressing Flag-HA tagged TP60. Affinity purification by using ant-Flag and anti-HA antibody was performed. Purified TIP60 complex was analyzed by SDS-PAGE and then the components of the TIP60 complex were determined by Mass Spectrometry analysis.

❸ SDS-PAGE analysis of the TIP60 complex by silver staining.

Laboratory of Chromatin Regulatory Network, Department of Mutagenesis,Radiation Biology CenterAssociate Professor : Tsuyoshi Ikura, D.D.S., Ph.D. TEL : +81-75-753-7556 FAX : +81-75-753-7564 e-mail : [email protected]

Department of Mutagenesis (Division of Chromatin Regulatory Network)

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Human genome is under constant threat of DNA damage inflicted by exogenous (i.e. ionizing irradiation) or endogenous (i.e. oxygen radical) agents. All cells are equipped with DNA damage signaling network to cope with this. We are studying molecular mechanisms in the hereditary disorders, such as Fanconi anemia or familial breast cancer, which have defects in the network.

Minoru Takata, M.D., Ph.D.Professor

Research and EducationGenome stability is crucial for maintaining integrity of the organism, and therefore all cells have elaborate systems to prevent, repair, or tolerate endogenous or exogenous DNA damage. In higher organisms, loss of the DNA damage signaling network often leads to cancer predisposition as well as impaired stem cell proliferation. A rare hereditary disorder Fanconi anemia (FA) is a prototype of such conditions. 13 genes have been implicated in FA, while mutation carriers of three FA genes develop familial breast cancer. We are trying to elucidate regulatory mechanisms and effecter function of genes involved in FA and familial breast cancer. In response to DNA damage, the key factors FancD2 and FancI are monoubiquitinated by a multi-subunit ubiquitin E3 ligase, consisting of at least ten proteins known as the FA core complex. In turn, FancD2 and FancI are both targeted to chromatin and form colocalizing foci, and function in DNA repair together with downstream molecule FancJ helicase. We have recently found that phosphoryation of FancI serves as a molecular switch to trigger monoubiquitinaion of FancD2. Now we are focusing on (1) how FancI is phosphorylated, (2) chromatin targeting mechanisms of FancD2, (3) the effecter function mediated by FancD2 and FancJ, (4) a role of FancJ in chromosome translocation.

Recent Publications1. Takata M, Ishiai M, Kitao H. The Fanconi anemia pathway: Insights from somatic cell genetics

using DT40 cell line. Invited review. Mutat Res. 2009 Jul 31;668(1-2):92-102. 2. Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, Saberi A, Kinoshita

E, Kinoshita-Kikuta E, Koike T, Tashiro S, Elledge SJ, & Takata M. FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat Struct Mol Biol. 2008 Nov;15(11):1138-46.

3. Ling C, Ishiai M, Ali AM, Medhurst AL, Neveling K, Kalb R, Yan Z, Xue Y, Oostra AB, Auerbach AD, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Takata M, Meetei AR, Wang W. FAAP100 is essential for activation of the Fanconi anemia-associated DNA damage response pathway. EMBO J. 2007 Apr 18;26(8):2104-14.

4. Kitao H, Yamamoto K, Matsushita N, Ohzeki M, Ishiai M, Takata M. Functional interplay between BRCA2/FANCD1 and FANCC in DNA repair. J Biol Chem. 2006 Jul 28;281(30):21312-20.

5. Matsushita N, Kitao H, Ishiai M, Nagashima N, Hirano S, Okawa K, Ohta T, Yu DS, McHugh PJ, Hickson ID, Venkitaraman AR, Kurumizaka H, Takata M. A FancD2-Monoubiquitin Fusion Reveals Hidden Functions of Fanconi Anemia Core Complex in DNA Repair. Mol Cell. 2005 Sep 16;19(6):841-7.

6. Hirano S, Yamamoto K, Ishiai M, Yamazoe M, Seki M, Matsushita N, Ohzeki M, Yamashita YM, Arakawa H, Buerstedde JM, Enomoto T, Takeda S, Thompson LH, Takata M. Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM. EMBO J. 2005 Jan 26;24(2):418-27.

❶ Co-localization of the core complex component FANCC and FANCD2. ❷ The phospho-mimic mutant of FANCI (Dx6) induced focus formation in a DNA damage-

independent manner. ❸ Member of the laboratory.

Late Effects StudiesRadiation Biology CenterProfessor : Minoru Takata, M.D., Ph.D. Associate Professor : Masamichi Ishiai, Ph.D. TEL : +81-75-753-7563 FAX : +81-75-753-7564 e-mail : [email protected] URL : http://www.rbc.kyoto-u.ac.jp/top.html

Late Effects Studies (Laboratory of DNA Damage Signaling)

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Current work in radiation biology, which started from the identification and isolation of genes responsible for radiation-sensitive human diseases, has revealed that the proteins which have a role in cellular radiation responses are also involved in a variety of important biological processes such as homologous recombination, DNA replication, cell cycle checkpoints, telomere maintenance. Our group is pursuing studies of repair gene networks starting with a NBS1 gene found to be responsible for a radiation sensitive disease. We would like to welcome serious students to join us if they are interested in helping to develop this new field of modern radiation biology.

Kenshi Komatsu, Ph.D.Professor

Research and EducationOur group is focusing on the biology of one protein in order to understand its multifunctional behavior in responding to DNA double-strand breaks, and the relationship of these breaks to a variety of pathways in living cells. Nijmegen breakage syndrome, characterized by a high sensitivity to DNA double-strand breaks and a predisposition to cancer, is a rare recessive genetic disease. NBS1, the underlying gene responsible for this disease, initiates homologous recombination repair in DNA by recruiting the Mre11/Rad50 nuclease to sites of DNA damage. NBS1 is also involved in cell growth and division through its regulation of S-phase and G2-phase checkpoints. Since damage repair is coordinated with cell growth, communication between DNA repair and checkpoint regulation functions is being investigated by the analysis of histone modifications. This modification process appears to be a unifying agent for the understanding of genome network function. Homologous recombination, inititated by the NBS1 gene, is an essential event for repair and meiotic recombination, and is also essential for the development of recombinant proteins, and thus another goal of our work is to understand the multiple pathways involved in homologous recombination and its regulation. Biological phenomena in living cells cannot be studied today by assigning each problem into a specific research area, and most problems studied today will be of interest or relevance to several different fields. Modern radiation biology is multidisciplinary area. Our goal of education is to support young scientists who take a multidisciplinary approach, and try to understand real biological events with the tools and methods available from a number of modern fields.

Recent Publications1. S. Matsuura, H. Tauchi, A. Nakamura, N. Kondo, S. Sakamoto, S. Endo, D. Smeets, B. Solder, B.

H. Belohradsky, V. M. D. Kaloustian, M. Oshimura, M. Isomura, Y. Nakamura, K. Komatsu (1998) Positional cloning of the gene for Nijmegen breakage syndrome. Nature Genet., 19: 179-181.

2. H. Tauchi, J. Kobayashi, K. Morishima, D. C. van Gent, T. Shiraishi, N. S. Verkalk, D. van Heems, E. Itoh, A. Nakamura, E. Sonoda, M. Takata, S. Takeda, S. Matsuura, K. Komatsu (2002) Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells, Nature, 420:93-98.

3. J. Kobayashi, H. Tauchi, S. Sakamoto, A. Nakmaura, K. Morishima, S. Matsuura, T. Kobayashi, K. Tamai, K. Tanimoto, K. Komatsu (2002) NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain. Curr. Biol., 12:1846-1851.

❶ NBS1, the product of the gene underlying the Nijmegen breakage syndrome, contains three functional regions: the forkhead associated (FHA) domain and CA1 C-terminus (BRCT) domain at the N-terminus, several SQ motifs (consensus phosphorylation sites by ATM and AT kinases) at a central region and MRE11-binding region at the C-terminus. The orthologs of NBS1 have not been identified in prokaryotes or archaebacteria, suggesting that this protein, especially the N-terminus, is unique to eukaryotic cell functions.

❷ NBS1 forms a multimeric complex with hMRE11/hAD50 nuclease at the C-terminus and recruits or retains them at the vicinity of sites of DNA damage by direct binding to histone H2AX, which is phosphorylated by ATM in response to DNA damage. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair and this process collaborates with cell-cycle checkpoints to facilitate DNA repair. The immunofluorescent staining indicated co-localization of gamma-H2AX foci and hME11 foci formation in wild type cells (low panel), but hMRE11 protein was confined in cytoplasm in NBS cells (upper right).

❸ Laboratory staffs

Genome DynamicsRadiation Biology CenterProfessor : Kenshi Komatsu Assistant Professor : Junya Kobayashi TEL : +81-75-753-7550 FAX : +81-75-753-7564 e-mail : [email protected] URL : http://www.rbc.kyoto-u.ac.jp/Genome/

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Genome Dynamics (Laboratory of Genome Dynamics)

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In human history, small organic molecules have been utilized for improving human health and for revealing secrets of life. Discovery or design of small organic molecules with unique biological activity permits small-molecule-initiated exploration of biology and further understanding of human diseases. Our laboratory has been discovering small organic molecules that modulate transcription or differentiation to use them as tools to explore biology. Such chemistry-initiated biology is recently called chemical biology, an emerging field of biology and medical sciences. Although our chemical biology is a basic one, it may “catalyze” future drug discovery.

Motonari Uesugi, Ph.D.Professor

Research and EducationOur laboratory attempts to make biomedical discoveries through the discovery, synthesis, and utilization of bioactive small organic molecules. Such small-molecule-init iated biology may provide a new avenue to a better understanding of biological events or diseases, and recently called chemical biology or chemical genetics. Our chemical biology investigation tackles a number of biomedical problems, including gene expression, cell differentiation, gene manipulation, cancer, and metabolic diseases. We hope to provide fresh insights into the understanding of these biological processes or diseases.

Our laboratory also provides rigorous research-based t r a in ing fo r g radua te s tuden t s and postdoctoral fellows in the fields of molecular biology, biochemistry, organic chemistry, analytical chemistry, and cell biology, and the investigators in the laboratory have distinct backgrounds from each other’s. Discussion with the investigators with different backgrounds in the laboratory usually leads to the initiation of our research projects.

Recent Publications1. Uesugi, M., Nyanguile, O., Lu, H., Levine, A. J., Verdine, G. L. Induced alpha-helix in the VP16

activation domain upon binding to a human AF. Science 277, 1310-1313 (1997). 2. Asada, S., Choi, Y., Yamada, M., Wang, S., Hung, M., Qin, J., Uesugi, M. External control of Her2

expression and cancer cell growth by targeting a Ras-linked coactivator. Proc. Natl. Acad. Sci. USA 99, 12747-12752 (2002).

3. Choi, Y., Kawazoe, Y., Murakami, K., Misawa, H., Uesugi, M. Identification of bioactive molecules by adipogenesis profiling of organic compounds. J. Biol. Chem. 278, 7320-7324 (2003).

4. Shimogawa, H., Kwon, Y., Mao, Q., Kawazoe, Y., Choi, Y., Asada, S., Kigoshi, H., Uesugi, M. A wrench-shaped synthetic molecule that odulates a transcription factor-coactivator interaction J. Am. Chem. Soc.126, 3461-3471 (2004).

5. Kwon, Y., Arndt, H., Mao, Q., Choi, Y., Kawazoe, Y., Dervan, P. B., Uesugi, M. Small molecule transcription factor mimic J. Am. Chem. Soc. 126, 15940-15941 (2004).

6. Choi, Y., Shimogawa, H., Murakami, K., Ramdas, L., Zhang, W., Qin, J., Uesugi, M. Chemical genetic identification of the IGF-linked pathway that is mediated by STAT6 and MFP2 Chemistry & Biology, 13, 241-249 (2006).

Chemical Biology Institute for Chemical ResearchProfessor : Motonari Uesugi Assistant Professor : Yoshinori Kawazoe, Hiroki Shimogawa TEL : +81-774-38-3225 FAX : +81-774-38-3226 e-mail : [email protected] URL : http://www.scl.kyoto-u.ac.jp/~uesugi/

Chemical Biology Division of Biochemistry

- Institute for Chemical Research


Our research focuses on the quality control mechanism of proteins in mammalian cells. Folding of newly synthesized proteins are assisted by molecular chaperones, and polypeptides that failed to obtain their native conformations are eventually degraded intracellularly. Under stress conditions such as heat shock and endoplasmic reticulum (ER) stress, polypeptides are denatured and prone to aggregate, which causes cellular insults. Cells are equipped with a sophisticated mechanism of quality control of proteins to maintain cellular functions and to prevent cell damage.

Research and EducationWe are working on the molecular mechanism of ERQC (ER quality control) and ERAD (ER-associated degradation) in mammals. Nascent polypeptides attain their native conformations by the assistance of molecular chaperones and folding enzymes in the ER, and sorted further into the secretory pathway. When proteins misfold irreversibly in the ER during the synthesis or by ER stress, they are recognized as terminally misfolded, and retrotranslocated to the cytosol through the unidentified dislocation channel. After ubiquitylation, misfolded polypeptides are degraded by the cytosolic proteasome. Most proteins synthesized in the ER are N-glycosylated, and ERQC of proteins also depends on the processing of N-glycans, which act as tags recognized by ER lectins. These mechanisms are conserved from yeast to mammals. Recently, many works have clarified the importance of ERAD of misfolded proteins and the disruption of ERQC in genetic diseases and neurodegenerative disorders. Our study will be performed from a broad point of view.

Recent Publications1. The role of MRH domain-containing lectins in ERAD. Hosokawa N, Kamiya Y, Kato K. Glycobiology, in press (2010) 2. EDEM1 accelerates the trimming of alpha1,2-linked mannose on the C branch of N-glycans. Hosokawa N, Tremblay LO, Sleno B, Kamiya Y, Wada I, Kato K, Nagata K, and Herscovics A.

Glycobiology: in press (2010) 3. Human OS-9, a lectin required for glycoprotein endoplasmic reticulum-associated degradation,

recognizes mannose-trimmed N-glycans. Hosokawa N, Kamiya Y, Kamiya D, Kato K, and Nagata K. J. Biol. Chem.: 284, 17061-17068

(2009) 4. Human XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L

ubiquitin ligase complex and BiP. Hosokawa N, Wada I, Nagasawa K, Moriyama T, Okawa K, and Nagata K. J. Biol. Chem.: 283,

20914-20924 (2008) 5. Simultaneous induction of the four subunits of TRAP complex by ER stress accelerates ER

degradation. Nagasawa K, Higashi T, Hosokawa N, Kaufman R J, Nagata K. EMBO Rep.: 8, 483-489 (2007)

❶ Q u a l i t y c o n t r o l mechanism in the ER

Fold ing of the newly synthesized proteins is assisted by molecular chaperones and folding enzymes in the ER, and only proteins with correct conformations are sorted further into the secretory pathway. When the proteins failed to fold correctly, they are retained in the ER and eventually degraded by ERAD.

❷ Involvement of N-glycans in the ER quality control

Most o f the prote ins s y n t h e s i z e d i n t h e ER are modif ied with N-glycans, and through recognition by specific lectins, oligosaccharides act as glycan signals for the quality control of glycoproteins.

❸ Intracellular localization of EDEM3

EDEM3 (Endoplasmic reticulum-degradation e n h a n c i n g a l p h a -m a n n o s i d a s e - l i k e protein-3) localizes in the ER.

Molecular and Cellular BiologyInstitute for Frontier Medical SciencesAssociate Professor : Nobuko Hosokawa TEL : +81-75-751-3849 FAX : +81-75-751-4646 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/

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Molecular and Cellular Biology Field of Biological Function

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- Institute for Frontier Medical Sciences


Our goal is to analyze the protein complex in the cell. We are analyzing transcription machinery that is most important and complicated system. To analyze the transcription machinery as a model of in vivo analysis, we are trying to develop a new technology, which is efficient in the cell.

Research and EducationAll phenomenon in the living cells are under the control of transcription. To understand the whole view of transcription machinery, we focused on the basal transcription. Transcription is a new and old problem in the lifescience field. A lots of scientists were tried to clarify the transcription in vitro. To understand the real reaction in the cell is still in the dark. To overcome the technical difficulties, we introduced a new technology RNA aptamer. This is an innovative technology to use an RNA as an analytical tool.RNA aptamer can bind to intra-cellular molecule including a protein using their tertiary structure. This molecule can penetrate into the cell to take full advantage of its compactness and can behave like as antibodies in the cell. The utility of this molecule is not only the analytical tool in the molecular biology, and is with great potentialoties as a therapeutic molecule. To apply the advantages of this molecule in the field of medical sciences and life sciences, we are developing software and hardware of application.

Recent Publications1. Chiba,Y et al.(2005)Cultured murine dermal fibloblast-like cells from senescence-accelerated

mice as in vitro models for higher oxidative stress due to mitochondrial alterations. J. Gerontol. A.Biol. Sci. Med. Sci. 60, 1987-1098

2. Li Z.Y. et al.(2000) Expression of N-deacetylase/sulfotransferase and 3-O-sulfotransferase in rat alveolar type II cells.Am. J. Physiolo. Lung Cell Mol. Physiol.279,L292-301.

3. Law,A. et al.(1998)Direct cloning of DNA that interacts in vitro with a specific protein application to RNA polymerase II and sites of pausing in Drosophila. Nucleic Acids Res. 26, 919-924.

4. Shopland L. S. et al.(1995)HSF access to heat shock elements in vivo dependends critically on promoter architecture defined GAGA factor, TFIID, and RNA polymerase II binding sites.9, 2756-2769.

❶ D e t e r m i n a t i o n of binding si te of RNA aptamer and expected structure Basal transcription factors on the gene.

❷ R N A a p t a m e r prevents the binding of factors and inhibits t h e fo r m a t i o n o f transcription.

Ultrastructural ResearchInstitute for Frontier Medical SciencesSenior Lecturer : Kazunori Hirayoshi TEL : +81-75-751-3840 FAX : +81-75-751-4646 e-mail : [email protected]

Ultrastructural Research Field of Biological Function

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Our Department is studying how the immune system controls physiological and pathological immune responses. Our main interest is in understanding the mechanism of immunologic unresponsiveness to self-constituents (i.e., immunologic self-tolerance) to determine the cause and mechanism of autoimmune disease, to develop the ways to provoke effective tumor immunity, and to establish stable immunologic tolerance to organ-transplants.

Shimon Sakaguchi, M.D., Ph.DProfessor

Research and EducationThe aim of this department in education and research is to provide a good opportunity for students to learn immunology and help them establish themselves as researchers in immunology and medicine. Our research is currently focused on understanding the mechanisms of immunologic self-tolerance (i.e. immunological unresponsiveness of the normal immune system to normal self-constituents). We specifically study: (i) the cellular and molecular basis of immunologic self-tolerance and the etio-pathology of autoimmune disease; (ii) the strategy for eliciting effective immune responses to autologous tumor cells, or inducing immunologic tolerance to organ transplants, by manipulating the mechanism of immunologic self-tolerance; and (iii) the cause and pathogenetic mechanism of rheumatoid arthritis by analyzing an animal model newly established in our laboratory.

Recent Publications1. Sakaguchi, S.: Naturally arising CD4+ regulatory T cells for immunologic self-tolelance and

negative control of immune responses. Ann. Rev. Immunol. 22:531-562, 2004. 2. Sakaguchi1, N., Takahashi1, T., Hata, H., Nomura, T., Tagami, T., Yamazaki, S., Sakihama, T.,

Matsutani, T., Negishi, I., Nakatsuru1, S., and Sakaguchi, S.: Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature. 426:454-60, 2003.

3. Hori, S., Nomura, T., and Sakaguchi, S.: Control of regulatory T cell development by the transcription factor Foxp3. Science. 299: 1057-1061, 2003.

4. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y., and Sakaguchi, S.: Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nature Immunol. 3: 135-142, 2002.

❶ Defects in immune regulation mediated by regulatory T cells cause autoimmune gastritis accompanying anti-parietal cell autoantibody, autoimmune thyroiditis, and insulitis of Langerhans’ islets of the pancreas as observed in human type 1 diabetes.

❷ Regulatory T cells control hazardous autoimmune T cells, thereby preventing autoimmune disease.

Experimental Pathology Institute for Frontier Medical SciencesProfessor : Shimon Sakaguchi TEL : +81-75-751-3851 FAX : +81-75-751-3820 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/bf03/

Experimental Pathology Field of Biological Function

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To understand the mechanisms regulating temporal and spatial generation of stem and progenitor cells within organs, we focus our analysis on microenvironmental niches for hematopoietic stem cells (HSCs) and progenitors and requisite signals provided by the niches, including the chemokine CXCL12 (SDF-1) and its receptor CXCR4. We utilize various techniques based on molecular biology, cellular biology, developmental biology and histology. The students are trained to be an excellent scientist, doing the research with us.

Takashi Nagasawa, M.D., Ph.D.Professor

Research and EducationChemokines are a large family of small structurally related cytokines that are thought to regulate cell trafficking and utilize seven- transmembrane spanning G-protein-coupled receptors (GPCR). We identified CXC chemokine ligand 12 (CXCL12), also known as stromal cell-derived factor (SDF)-1 as pre-B-cell growth stimulating factor and found that CXCL12 and its primary receptor CXCR4 are essential for hematopoiesis, including colonization of bone marrow by hematopoietic stem cells (HSCs) during ontogeny, maintenance of the HSC pool in adult bone marrow and development of B lymphocytes and plasmacytoid dendritic cells (pDCs) as well as cardiogenesis and organ vasculalization during ontogeny (4,5). Recently, we have identified a small population of non-hematopoietic cells expressing high amounts of CXCL12, termed CXCL12-abundant reticular (CAR) cells with long processes. We have revealed that CAR cells are scattered throughout bone marrow and that most HSCs, early B cell precursors, the end-stage B lymphocyte plasma cells and pDCs are attached to the processes of CAR cells and that CAR cells are adipo-osteogenic progenitors, which function as the special microenvironments, termed ‘niches’ for HSCs and hematopoietic progenitors (1-3). We educate students in research, reading of papers and discussion.

Recent Publications1. Omatsu, T., Sugiyama, T., Kohara, H., Kondoh, G., Fujii, N., Kohno,, K., *Nagasawa, T. The

Essential Functions of Adipo-osteogenic Progenitors as the Hematopoietic Stem and Progenitor Cell Niche.

Immunity 33; 387-399, 2010. 2. Sugiyama, T., Kohara, H., Noda, M., and *Nagasawa, T. Maintenance of the Hematopoietic Stem

Cell Pool by CXCL12-CXCR4 Signaling in Bone Marrow Stromal Cell Niches. Immunity 25; 977-988. 2006. 3. Tokoyoda, K., Egawa, T., Sugiyama, T., Byung-I1 Choi and *Nagasawa, T. Cellular niches

controlling B lymphocyte behavior within bone marrow during development. Immunity 20; 707-718, 2004 4. Tachibana, K., Hirota, S., Iizasa, H., Yoshida, H., Kawabata, K., Kataoka, Y., Kitamura, Y.,

Matsushima, K., Yoshida, N., Nishikawa, S., Kishimoto, T., and *Nagasawa, T. The chomokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract.

Nature 393: 591-594, 1998. 5. *Nagasawa, T., Hirota, S., Tachibana, K., Takakura, N., Nishikawa, S.-I., Kitamura, Y.,Yoshida, N.,

Kikutani, H., and Kishimoto, T. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1.

Nature 382: 635-638, 1996

❶ CXCL12-CXCR4 signaling is essential for homing of HSCs and primordal germ cells (PGCs) to the bone marrow and gonads, respectively during ontogeny and might be involved in cancer metastasis, colonization of cancer stem cells in the adult.

❷ CAR cells, expressing high levels of CXCL12 have long processes. ❸ Model of niches for HSCs and lympho-hematopoietic cells. ❹ Laboratory members.

Immunobiology and HematologyInstitute for Frontier Medical SciencesProfessor : Takashi Nagasawa Assistant Professor : Tatsuki Sugiyama TEL : +81-75-751-4100 FAX : +81-75-751-4820 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/se03/

index-e.html

Immunobiology and Hematology Field of Biological Function

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With the advent of the aging society, movement disorder and dementia are becoming major targets in mordern health care and medicine. Our research efforts are focused on the elucidation of molecular mechanisms underlying formation and regeneration of tissues in locomotive organs such as bone, cartilage, and tendon/ligaments with the molecular approaches based on developmental biology and cell biology.

Yuji Hiraki, Ph.D.Professor

Research and EducationIn general, mesenchymal tissues contain a well-developed network of capillaries. However, cartilage is resistant to vascular invasion from surrounding tissues and is usually kept avascular except for the vascular invasion into cartilage during endochondral bone formation. Similarly, tendons and ligaments are known to be hypovascular. In our laboratory, we identified chondromodulin-I for the first time as a tissue-specific angiogenesis inhibitor in cartilage. Molecular cloning of the chondromodulin-I related gene enabled us to identify another tissue-specific anti-angiogenic molecule Tenomodulin, which is specifically expressed in tendons and ligaments. We think it important to understand what is the nature of hypovascularity in mesenchymal structures and how it plays a role in the body during development and regeneration of musculoskeletal organs.Our current research efforts are focused on the following studies: 1) mechanism of replacement of cartilage by bone during endochondral bone formation; 2) identification of novel genes associated with chondrogenic differentiation by global analysis of gene expression; 3) mechanism underlying regeneration of articular cartilage; 4) molecular mechanism of tendon/ligament development; 5) action mechanisms of tissue-specific anti-angiogenic factors and their therapeutic applications for angiogenic diseases.

Recent Publications1. Miura S, Mitsui K, Heishi T, Shukunami C, Sekiguchi K, Kondo J, Sato Y, Hiraki Y (2010)

Impairment of VEGF-A-stimulated lamellipodial extensions and motility of vascular endothelial cells by Chondromodulin-I, a cartilage-derived angiogenesis inhibitor. Exp Cell Res, 316: 775-788

2. Takimoto A, Nishizaki Y, Hiraki Y, Shukunami C (2009) Differential actions of VEGF-A isoforms on perichondrial angiogenesis during endochondral bone formation. Dev Biol 322: 196-211

3. Shukunami C, Takimoto A, Miura S, Nishizaki Y, Hiraki Y (2008) Chondromodulin-I and tenomodulin are differentially expressed in the avascular mesenchyme during mouse and chick development. Cell Tissue Res 332: 111-122

4. Mori H, Shukunami C, Furuyama A, Notsu H, Nishizaki Y, Hiraki Y (2007) The immobilization of bioactive FGF-2 into cubic proteinous micro-crystals (Bombyx mori cypovirus polyhedra) that are insoluble in a physiological cellular environment. J Biol Chem 282: 17289-17296

5. Shukunami C, Takimoto A, Oro M, Hiraki Y (2006) Scleraxis positively regulates the lineage-specific expression of tenomodulin, a marker of tenocytes. Dev Biol 298: 234-247

❶ Differentiation of mesenchymal stem cells ❷ Fish facility for Medaka and Zebrafish. Medaka and zebrafish are excellent model organisms for elucidating developmental

processes due to the transparency of embryos. Current projects in our laboratory are to reveal role of chondromodulin-I, cartilage-derived angiogenesis inhibitor, in vascular development and molecular mechanism of cartilage development.

❸ Laboratory members

Cellular DifferentiationInstitute for Frontier Medical SciencesProfessor : Yuji Hiraki Associate Professor : Chisa Shukunami TEL : +81-75-751-4608 FAX : +81-75-751-4633 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/

te01/index-j.htm

Cellular Differentiation Field of Tissue Engineering

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This laboratory analyzes molecular and cellular mechanisms to control function of stem cells and differentiation of mammalian germ cells by using various mouse strains. Particular attention is paid to the development of embryonic germ cells and spermatogenic cells in testes, as well as pluripotent embryonic stem cells. Also, we are the only group in Japan carrying out the establishment and distribution of human embryonic stem cell lines. So far, we have established and characterized five human ES cell lines, and we have distributed cell lines to about 50 research projects since March 2004.

Norio Nakatsuji, D.Sc.Professor

Research and EducationThe succession between germ cells and pluripotent cells are fundamentals for ontogeny of individuals and continuity through generations. Molecular mechanisms underlying the germ-line cells serve as basal states for the derivation of somatic cell lineages. We aim to elucidate such basic molecular systems underlying in the germ-line cells, and are currently focusing on cytoplasmic RNP structures in the germ cells, called nuage or germ granules, through the identification and functional analyses of the specific components. We have shown that (1) proteins containing multiple Tudor domains, TDRD1/MTR1, TDRD6 and TDRD7/TRAP in mice specifically localize to germ granules/nuage during spermatogenesis, (2) a single Tudor domain is sufficient for the localization to germ granules/nuage, but its over-expression causes meiotic defect during spermatogenesis, (3) spliceosomal complex snRNPs accumulate to germ granules/nuage during spermatogenesis and form complex with TDRD1, (4) mice homozygous for a targeted mutation of Tdrd1 are male-sterile, and (5) the localization of TDRD1 to germ granules/nuage is under the control of Mvh activity. Further analyses on these mammalian tudor-related genes are in progress. We are also trying to isolate specific components of germ granules/nuage by proteomics/transcriptome analyses. Also, we are the only group in Japan carrying out important activities of the establishment and distribution of human embryonic stem cell lines. We have obtained the approval and national grants to produce human ES cell lines in April 2002. So far, we have established and characterized five human ES cell lines (KhES-1, -2, -3,-4, -5). We have distributed cell lines to about 50 research projects since March 2004. Such distributed human ES cells will be used for many aspects of the biomedical research. Recent Publications

1. Hosokawa, M., Shoji, M., Kitamura, K,. Tanaka, T., Noce, T., Chuma, S., Nakatsuji, N. Tudor-related proteins TDRD1/MTR-1, TDRD6 and TDRD7/TRAP: Domain composition, intracellular localization, and function in male germ cells in mice. Dev. Biol. 301, 38-52 (2007).

2. Nakatsuji, N., Nakajima, F., Tokunaga, K. HLA-haplotype banking and iPS cells. Nature Biotechnol. 26, 101-106 (2008).

3. Miyazaki T, Futaki S, Hasegawa K, Kawasaki M, Sanzen N, Hayashi M, Kawase E, Sekiguchi K, Nakatsuji N, Suemori H. Recombinant human laminin isoforms can support the undifferentiated growth of human embryonic stem cells. Biochem Biophys Res Commun. 375, 27-32 (2008).

4. Yamauchi, K., Hasegawa, K., Chuma, S., Nakatsuji, N. and Suemori, H. In vitro germ cell differentiation from cynomolgus monkey embryonic stem cells. PLoS ONE 4, e5338 (2009).

5. Shoji, M., Tanaka, T., Hosokawa, M., Reuter, M., Stark, A., Kato, Y., Kondoh, G., Okawa, K., Chujo, T., Suzuki, T., Hata, K., Martin, S. L., Noce, T., Kuramochi-Miyagawa, S., Nakano, T., Sasaki, H., Pillai, R. S., Nakatsuji, N. and Chuma, S. The TDRD9-MIWI2 complex is essential for piRNA-mediated retrotransposon silencing in the mouse male germline. Developmental Cell 17, 775-787 (2009).

❶ Ribonucleoprotein-rich granules in the cytoplasm of germ cells, showing specific localization of one of the components (green).

❷ Ribonucleoprotein-rich granules in the cytoplasm of germ cells, showing specific localization of one of the components (green).

❸ Members

Development and Differentiation Institute for Frontier Medical SciencesProfessor : Norio Nakatsuji Senior Lecturer : Eihachiro Kawase Assistant Professor : Shinichiro Chuma TEL : +81-75-751-3821 FAX : +81-75-751-3890 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/

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Development and Differentiation Field of Regeneration Control

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Cellular differentiation and tissue formation during development of muticellular organisms including human require cell-cell communications and interactions. Investigations of our lab focus on molecular mechanisms that govern such cellular interactions, which play roles in cellular differentiation, tissue formation, and organogenesis. 1)Molecular mechanisms of cellular differentiation and organogenesis of mesodermal tissues including skeletal muscle, heart, and adipose tissue. 2)Myogenesis during development and regeneration, muscle stem cells3)Roles of ADAM genes in organogenesis and diseases.

Atsuko Sehara-Fujisawa, Ph.D.Professor

Research and Education■Topics of Our ResearchCurrent topics of our research are on the roles of ADAM proteases in organogenesis. Numerous intercellular signaling molecules are generated as membrane-anchored proteins, and they are subjected to proteolytic processing to liberate their extracellular domains (These phenomena is called as ectodomain sheddings). Molecular bases that regulate the ectodomain shedding processes are coming into focus since discovery of ADAM family proteins that participate in the ectodomain shedding through their protease domains. Our lab is one of pioneer groups in the world who have identified and investigated the roles and functions of ADAM proteins in development. We found that Meltrin alpha and beta, members of ADAM proteins, are involved in the liberation of soluble ErbB ligands from membrane-anchored growth factors. Meltrin alpha play roles in myogenesis and adipogenesis while Meltrin beta is involved in neurogenesis and the heart formation. Thus, metalloproteases of Meltrins work as scissors to modulate intercellular signalings necessary for organogenesis through generation of soluble growth or differentiation factors from membrane-anchored precursor molecules. Numerous ADAM genes are found in human genome. We hope to reveal significance of ectodomain sheddings mediated by ADAM proteases and their regulatory mechanisms in development and diseases.

Recent Publications1. Sunadome, K., Yamamoto, T., Ebisuya, M., Kondoh, K., Sehara-Fujisawa., A., Nishida, E.. ERK5

Regulates Muscle Cell Fusion through Klf Transcription Factors. Dev. Cell, in press 2. Iida, A., Sakaguchi, K., Sato, K., Sakurai, H., Nishimura, D., Iwaki, A., Takeuchi, M., Kobayashi,

M., Misaki, K., Yonemura, S., Kawahara, A., and Sehara-Fujisawa, A.. Metalloprotease-Dependent Onset of Blood Circulation In Zebrafish. Current Biol., 22;20(12):1110-6. (2010)

3. Wakatsuki, S., Yumoto, N., Komatsu, K., Araki, T., Sehara-Fujisawa, A.. : Roles of meltrin beta /ADAM19 in progression of Schwann cell differentiation and myelination during sciatic nerve regeneration. J Biol Chem. (2008)

4. Yumoto, N., Wakatsuki, S,. Kurisaki, T., Hara, Y., Osumi, N., Frisén, J., Sehara-Fujisawa, A.. : Meltrin beta/ADAM19 interacting with EphA4 in developing neural cells participates in formation of the neuromuscular junction. PLoS ONE, 3(10): e3322. (2008)

5. Weskamp, G., Ford, J.W., Sturgill, J., Martin, S.,Docherty, A., Swendeman, S., Broadway, N., Hartmann,D., Saftig, P., Umland, S., Sehara-Fujisawa, A., Black, R.A., Ludwig, A., Becherer, J.D., Conrad, D.H. and Blobel, C.P. : ADAM10 is a principal ‘shedase’ of the low-affinity immunoglobulin E receptor CD23. nature immunology, ;7(12):1293-1298. (2006)

❶ (left panel) The meltrin alpha knockout mouse shows mild resistance to high fat-diet induced obesity. (left panel) Meltrin beta is involved in the heart development.

❷ ADAM proteases work as scissors that generate soluble growth or differentiation factors from membrane-anchored precursor molecules.

❸ The onset of blood circulation. Live imaging of zebrafish embryos revealed the synchronous onset of blood circulation. Protease activity of ADAM8 regulates the onset of blood circulation by abrogation of blood-blood vessel adhesion

❹ Staffs and graduate students

Department of Growth Regulation Institute for Frontier Medical SciencesProfessor : Atsuko Sehara-Fujisawa Assistant Professor : Tomohiro Kurisaki, Atsuo Iida TEL : +81-75-751-3826 FAX : +81-75-751-4642 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/

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Growth Regulation Field of Regeneration Control

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T cells develop in thymus and are main players in the field of the cellular immunity. Sub-lethal irradiation or administration of chemical mutagens to mice causes them severe thymic atrophy. Later the thymus regenerates by the supply of stem cells from bone marrow. However, thymic lymphoma often emerges during the process. We have been investigating the tumorigenic differences for X-ray induced and ENU induced thymic lymphomas. We are also interested in unraveling the mechanism of T cell receptor (TCR) beta chain gene rearrangement and are intensively analyzing the gene segments used for recombination in the murine thymic lymphomas.

Research and EducationTCRbeta chain gene rearrangement is ordered; first, D to J rearrangement occurs on both alleles, then, one of the alleles initiates V to DJ rearrangement. We have established a method to detect the V, D and J segments recombined for TCRbeta chain genes utilizing PCR. As shown in Figure, D to J rearrangement yields two types of DJ alleles. Molecular processes of how these two constructs are made are poorly understood and even which is dominantly formed has not been clearly shown. Our recent analyses of two series of murine thymic lymphomas have revealed the ratio of these two DJ alleles. Moreover we have obtained the data indicating that occurrences of V to DJ rearrangement from each allele are not the same (Table). A T cell expresses cell surface TCRbeta chains from a single allele due to “allelic exclusion”. To achieve allelic exclusion, it is assumed that V to DJ rearrangement does not take place on both alleles simultaneously. Our data, however, suggest it is not always applicable that initiation of V to DJ rearrangement occurs on one allele at a time. Elucidating the precise molecular mechanisms of allelic exclusion is our final goal.

Recent Publications1. Ikawa, T., Fujimoto, S., Kawamoto, H., Katsura, Y. and Yokota, Y. (2001) Commitment to natural

killer cells requires the helix-loop-helix inhibitor Id2. Proc. Natl. Acad. Sci. USA. 98:5164-6169. 2. Kawamoto, H., Ohmura, K. Fujimoto, S., Lu, M., Ikawa, T. and Katsura, Y. (2003) Extensive

proliferation of T cell lineage-restricted progenitors in the thymus: an essential process for clonal expression of diverse T cell receptor beta chains. Eur. J. Immunol. 33:606-615.

3. Fujimoto, S., Ikawa, T., Kina, T. and Yokota, T. (2007) Forced expression of Id2 in fetal thymic T cell progenitors allows some of their progeny to adopt NK cell fate. Int. Immunol. 19:1175-1182.

4. Tokuriki, A., Iyoda, T., Inaba, K., Ikuta, K., Fujimoto, S., Kumakiri, M. and Yokota, T. (2009) Dual role for Id2 in chemical carcinogen-induced skin tumorigenesis. Carcinogenesis 9:1645-1650.

❶ Figure DJ alleles and VDJ alleles in TCRbeta locus TCRbeta chain gene D to J rearrangement can generate two types of DJ alleles. Two

types of VDJ alleles from DJ (I) allele and one from DJ (II) allele can be formed by the following V to DJ rearrangement.

❷ Table The occurrences of V to DJ rearrangement from DJ (I) / DJ (I) and DJ (II) / DJ (II) allele

It was impossible to figure out separately the occurrences for alphabeta T cells based on the other group’s data.

ImmunologyInstitute for Frontier Medical SciencesAssistant Professor : Shinji Fujimoto TEL : +81-75-751-3845 FAX : +81-75-751-4648 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/rc04/

Immunology Fields of Regeneration Control

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“All research should stem from clinical diseases.” is the basic concept of our department. This does not mean that all researchers should have a medical background, but that all researches should be designed based on the pathological condition of target diseases. Current medical procedures are requested to have molecular evidences to support their validity, as represented by the term “Evidence Based Medicine”. Application of regenerative medicine should not be performed without comprehensive understanding of biological events required for the process of regeneration for each tissue. Following these requirements, we are investigating biological events during the regeneration of mesenchymal tissues to develop innovative therapeutic modalities.

Junya Toguchida, M.D., Ph.D.Professor

Research and EducationThe major role of mesenchymal tissues such as bone, cartilage, and muscle is to compose the stature specific for each multicellular organism, but they also provide appropriate platforms for epithelial tissues, creating the communication to receive and transmit important signals for the maintenance of homeostasis. Tissue regeneration is a biological phenomenon accomplished by a number of players including those who do not participate in the development of each tissue, and the contribution of each player is strictly regulated both in time and place. It is a crucial process in multicellular organisms for their survival, but also has a risk to trigger the unregulated cell growth, which might finally become neoplasms. Osteosarcoma, for example, is one of malignant tumors of bone, and created by the proliferation of tumor cells with osteoblastic phenotype, which produced the bone matrix. Pathological findings have several similar features with the process of fracture healing. The primary investigator of this field is an orthopaedic surgeon dealing with the treatment of patients with malignant mesenchymal tumors, and also engaging in related basic researches, especially in genetic alterations involved in carcinogenesis. One of unique characters of our department is that researches for regenerative medicine and for oncology, which are tightly linked to each other, are investigated in the same laboratory, even by a same researcher, making it possible to share technologies and inspire each other for developing a new cutting edge. The establishment of immortalized mesenchymal stem cell lines by oncogenic virus protein is one of examples, and recent topic is the common features of cancer stem cells and tissue stem cells. Since 2008, the clinical trial based on our previous animal experiments are launched, which we believe is an important step toward the realization of our aim “bring the information “from bed side to bench side”, and apply the new therapeutic modalities “from bench side to bed side”. In addition, the PI has joined the Center for iPS Research and Application (CiRA) as a faculty, which will enlarge the field of stem cell biology in our department. We are welcome to cooperate with researchers who share our aim irrespective of their background and also to have young powers to join us.

Recent Publications1. Ikeguchi, R., et al. (2006) Regeneration of osteonecrosis of canine scapho-lunate using bone

marrow stromal cells: possible therapeutic approach for Kienböck disease. Cell Transplantation, 15:411-22.

2. Shibata KR et al. (2007) Expression of the p16INK4A gene is associated closely with senescence of human mesenchymal stem cells, and potentially silenced by DNA methylation during in vitro expansion. Stem Cells, 25:2371-82.

3. Toguchida J, Nakayama T. (2009) Molecular genetics of sarcomas: Applications to diagnoses and therapy. Cancer Sci 100:1573-80.

4. Otsuka S, et al. (2009) PGE2 signal via EP2 receptors evoked by a selective agonist enhances regeneration of injured articular cartilage Osteoarthritis Cartilage, 17:529-38.

5. Ito K, et al. (2009) A novel method to isolate mesenchymal stem cells from bone marrow in a closed system using a device made by non-woven fabric. Tissue Eng Part C Methods, in press.

❶ Induction of iPS cells from bone marrow stromal cells. Using bone marrow stromal cells (B) from patients suffering bone and cartilage diseases with no appropriate treatments, we are inducing iPS cells (A) to investigate the pathology and develop new treatments.

❷ Photo of members in the department ❸ Clinical trials of the application of mesenchymal stem cells for the treatment of

osteonecrosis of femoral head.

Tissue Regeneration Institute for Frontier Medical SciencesProfessor : Junya Toguchida TEL : +81-75-751-4134 FAX : +81-75-751-4134 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/

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Tissue Regeneration Field of Clinical Application

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This department was founded immediately after the establishment of the Institute in 2002 by Professor Kazutomo Inoue who moved, with his colleagues, from the First Department of Surgery, Kyoto University. Since then, we have been studying regenerative medicine for endocrine and metabolic diseases including diabetes mellitus in relation with islet and pancreas transplantation. The final goal of our study is to establish regenerative medicine for diabetes mellitus, which should be a safe and effective therapy available whenever and wherever required for a growing number of diabetes patients world-wide. To this goal, we are studying bio-artificial pancreas and other topics including cell therapy by various stem cells and novel transplantation methods using biomaterials.

Research and EducationThis department has received undergraduate, master’s and doctoral students as well as postdoctoral fellows and foreign researchers. We have established isolation method of rat and porcine islets and successfully shown the efficacy of several macro-devices of bioartificial pancreas. In contrast to micro-encapsulation that is irretrievable after inplantation, macro-devices are retrievable and exchangeable, which is important advantage toward clinical application. In our past studies, mesh-reinforced polyvinyl alcohol (PVA) tube and bag, rod-shaped device of agarose-based gel and so on were investigated in allo- and xeno-geneic situations. We have also shown that the subcutaneous site pretreated for angiogenesis can be successfully used for transplantation site of these devices, leading to long-term normalization of blood glucose levels in diabetic rodents. Recently we developed a novel method to make a sheet-shaped PVA-macroencapsulated islets by a combination of the freezing technique of islets and the phenomenon that PVA solution becomes gel by freezing and thawing and are studying this toward application to bigger animals and humans. We are also studying chitosan-based biomaterials for transplantation of islets or artificial beta-cells to subcutaneous and miscellaneous sites. In addition, we are studying various cell sources for cell therapy of diabetes mellitus. These studies include beta-cell differentiation form ES, iPS and other stem cells using human artificial chromosome (collaborative study with Professor Oshimura, Tottori University) cell fusion between islet cells and mesenchymal stem cells, showing several promising findings therapy.

Recent Publications1. Yang KC, Qi Z, Wu CC, Shirouza Y, Lin FH, Yanai G, Sumi S. The cytoprotection of chitosan

based hydrogels in xenogeneic islet transplantation: An in vivo study in streptozotocin-induced diabetic mouse. Biochem Biophys Res Commun. 393(4): 818-823, 2010.

2. Qi Z, Shen Y, Yanai G, Yang K, Shirouzu Y, Hiura A, Sumi S. The in vivo performance of polyvinyl alcohol macro-encapsulated islets. Biomaterials 31(14): 4026-4031, 2010.

3. Yang KC, Wu CC, Lin FH, Qi Z, Kuo TF, Cheng YH, Chen MP, Sumi S. Chitosan/gelatin hydrogel as immunoisolative matrix for injectable bioartificial pancreas. Xenotransplantation. 15(6): 407-416, 2008.

4. Sakata N, Gu Y, Qi M, Yamamoto C, Hiura A, Sumi S, Sunamura M, Matsuno S, Inoue K. Effect of rat-to-mouse bioartificial pancreas xenotransplantation on diabetic renal damage and survival. Pancreas. 32(3): 249-257, 2006.

5. Shirouzu Y, Gu Y, Koga M, Sakurai T, Qi M, Hiura A, Sumi S, Inoue K. Cold preservation of islets in UW solution--with special reference to apoptosis. J Surg Res. 133(2):167-175, 2006.

❶ Mesh-reinforced PVA-macroencapsulated islets (right: microscopic view of dithizone-staining)

Associate Professor : Shoichiro Sumi Assistant Professor : Yasumasa Shirouzu TEL : +81-75-751-4856 or 4848 FAX : +81-75-751-4156 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/ca03/

Organ Reconstruction Field of Clinical Application

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We have devised a completely new approach so called “in situ Tissue Engineering” to the development of artificial organs. The extracellular matrix (ECM) or reconstitutes the solid structure from the extracted collagen is employed as a scaffold, which after implantation into the patients is used for the regeneration or re-differentiation of tissue. We have already carried out successful trials at regenerating the trachea and peripheral nerves etc. with this method. Our pioneering work is expected to be a major area of medical science for the coming generation.

Research and EducationWe consider that mammals do not, in fact, lose their ability to regenerate, and that the potential is hidden by excessively rapid wound healing around the failing tissues. In this sense, if we can provide good conditions using a scaffold, we can induce this hidden potential even in higher mammals. In tissue engineering, three main components are used: (1) cells, (2) a scaffold, and (3) growth factors. We have advocated a new approach – in situ tissue engineering – whereby tissue is made in the living body, rather than in a culture bottle. To obtain the purified ECM, cell components are completely removed from homo or allo-organs. The solid structure is reconstituted from the ECM and extracted collagen. Growth factors are then applied to facilitate cell proliferation. Then this ECM-collagen-growth factor composite is implanted into the living body as a temporary scaffold for new organ regeneration. Besides this, bioabsorbable materials will also be applied instead of purified ECM as a bulk structure for organ regeneration. Both extracted collagen and growth factors are should facilitate cell proliferation and cell redifferentiation, leading to regeneration of organs completely composed of cells derived from patients.

Recent Publications1. Shimada, H., Nakada, A., Hashimoto, Y., Shigeno, K., Shionoya, Y., Nakamura, T.: Generation

of canine induced pluripotent stem cells by retroviral transduction and chemical inhibitors. Mol Reprod Dev. 77(1): 2 (2010)

2. Nakamura, T., Sato, T., Araki, M., Ichihara, S., Nakada, A., Yoshitani, M., Itoi, S., Yamashita, M., Kanemaru, S., Omori, K., Hori, Y., Endo, K., Inada, Y., Hayakawa, K.: In situ tissue engineering for tracheal reconstruction using a luminar remodeling type of artificial trachea. J Thorac Cardiovasc Surg. 138(4): 811-819 (2009)

3. Nakada, A., Fukuda, S., Ichihara, S., Sato, T., Itoi, S., Inada, Y., Endo, K., Nakamura, T.: Regeneration of central nerves using a collagen scaffold and adipose-derived stromal cells. Cells Tissues Organs. 190(6): 326-335 (2009)

4. Sato, T., Tao, H., Araki, M., Ueda, H., Omori, K., Nakamura, T.: Replacement of the left main bronchus with a tissue-engineered prosthesis in a canine model. Ann Thorac Surg. 86(2): 422-428 (2008)

5. Kin, S., Hagiwara, A., Nakase, Y., Kuriu, Y., Nakashima, S., Yoshikawa, T., Sakakura, C., Otsuji, E., Nakamura, T., Yamagishi, H.: Regeneration of skeletal muscle using in situ tissue engineering on an acellular collagen sponge scaffold in a rabbit model. ASAIO J. 53(4): 506-513 (2007)

❶ Generation of iPS(induced pluripotent stem) cells from canine fibroblasts ❷ Generation of neurons from canine iPS cells ❸ Regeneration of central nerves using a collagen scaffold and adipose-derived stromal

cells (ASCs)

Bioartificial OrgansInstitute for Frontier Medical SciencesAssociate Professor : Tatsuo Nakamura Part-timeLecturer : Katsumi Hayakawa, Keiji Shigeno, Yuji Inada, Yoshio Hori, Akeo Hagiwara TEL : +81-75-751-4149 FAX : +81-75-751-4844 e-mail : [email protected] URL : http://www.frontier.kyoto-u.ac.jp/ca04/

Bioartificial Organs Field of Clinical Application

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Our laboratory is dedicated to methodology development for single-molecule observation and manipulation at nanometer precisions in living cells. The development is carried out simultaneously with the application for the studies of nano-bioprocesses occurring in living cells, in particular, signal transduction in the cell membrane and the formation and remodeling of the neuronal network. The smooth liaison between physics/engineering and biomedicine is a key for our methodology developments. On the basis of the knowledge of nano-bioprocesses learned in the cells (e.g., partitioning of the plasma membrane into submicron compartments and transient formation of signaling platforms in the cell membrane) and the single-molecule bionanotechnology developed here, we envisage the next-generation nanotechnology, regenerative medicine, and drug discovery protocols. Akihiro Kusumi, D. Sc.

Professor

Research and EducationThe cell is surrounded by the cell membrane, and it is responsible for exchanging information, energy, and molecules with the outside world. Furthermore, 40% of cellular reactions take place in the membrane, and 30% of energy is stored in a form of the concentration gradient across the membrane. These functions are carried out by biomolecular nanosystems, but how exactly they are done is unknown. As described at the end of this part, these membranes have incredibly peculiar structures, and the cell appears to make the cell membrane work by taking advantage of the very peculiar structural features of the cell membrane.

We at the Kusumi laboratory are trying to understand the basic mechanisms for the function of the cell membrane at a very fundamental level. One of the most important features of our projects is to develop and apply single-molecule tracking/manipulation techniques (single-molecule nanobiotechnology) for the studies of living cells.

Our study is based on a hypothesis that “three fundamental physical properties of the cell membrane are essentially responsible for its function”. They are: (1) its low (two) dimensionality greatly facilitates molecular collisions, (2) molecular complexes and micro(nano)domains with various sizes and lifetimes continually form and disintegrate, and (3) the cell membrane is partitioned into many small compartments due to the presence of the actin-based membrane skeleton fence and anchored transmembrane protein pickets aligned along the membrane skeleton. In our laboratory, we hope to better define these three properties, and at the same time, to understand how these properties make possible the functions of the cell membrane, i.e., to reveal the “Membrane Mechanisms”.

Recent Publications1. N. Morone et al. Three-dimensional reconstruction of the membrane skeleton at the plasma

membrane interface by electron tomography. J. Cell Biol. 174, 851-62 (2006). 2. K. G. N. Suzuki et al. GPI-anchored receptor clusters transiently recruit Lyn and Gα for temporary

cluster immobilization and Lyn activation: single-molecule tracking study 1. J. Cell Biol. 177, 717-730 (2007).

3. K. G. N. Suzuki et al. Dynamic recruitment of phospholipase Cγ at transiently immobilized GPI-anchored receptor clusters induces IP3-Ca2+ signaling: single-molecule tracking study 2. J. Cell Biol. 177, 731-742 (2007).

4. K. A. K. Tanaka et al. Membrane molecules mobile even after chemical fixation. Nature Methods 7, 865-866 (2010).

5. R. S. Kasai et al. Full characterization of GPCR monomer-dimer dynamic equilibrium by single molecule imaging. J. Cell Biol. 192, 463-480 (2011).

❶ F igure 1 . Le f t . S ing le -molecu le tracking. A fluorescent or colloidal gold tag is attached to a membrane protein or a lipid molecule by way of a specific antibody’s Fab fragment or a ligand, and their movement in the cell membrane is visualized. Right. Using an optical trap (laser tweezers), a membrane molecule tagged by a gold particle is moved at will along the cell membrane, by moving the laser tweezers that trap the gold particle. The force exer ted on this single molecule from the membrane skeleton or microdomains is registered at every pixel.

❷ Figure 2. Inactive signaling protein Ras, located on the cytoplasmic surface of the plasma membrane (green), undergoes regulated Brownian diffusion (yellow trajectories). By the method we developed, the activation of this single Ras molecule was imaged (green color changes to red, due to FRET, at the center of this image), which entails the first successful observation of the activation of a single molecule. Many other cytoplasmic molecules are recruited to this activated Ras molecule, inducing immobilization of this activated Ras signaling complex. Su r p r i s ing l y, such a mo lecu la r complex disintegrates within a second, suggesting a possibility that the basic unit of the cellular signal occurs like a digital pulse. Such observations are only possible with single-molecule imaging, rather than observing the average behavior of many molecules.

❸ F i g u r e 3 . A d i s c o v e r y, w h i c h necessitated a paradigm shift of the concept of the plasma membrane structure and function, has been made. The entire plasma membrane i s p a r t i t i o n e d i n t o m a ny s m a l l compar tmen ts o f 30 – 200 nm (depending on the cell type) due to the actin-based membrane skeleton (fence, left) and var ious transmembrane proteins anchored to the membrane skeleton (pickets, right).

Nano BioprocessesResearch Center for Nano Medical EngineeringInstitute for Frontier Medical SciencesProfessor : Akihiro Kusumi Associate Professor : Takahiro Fujiwara, Kenichi Suzuki TEL : +81-75-751-4112 FAX : +81-75-751-4113 e-mail : [email protected] URL : http://www.nanobio.frontier.kyoto-u.

ac.jp

Nano Bioprocesses Research Center for Nano Medical Engineering

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Not only gravity, but many kinds of dynamic environment are influential in the function of living bodies. The dynamic environment is mainly essential for the human body, but occasionally it may become a danger of impairments. However, the total mechanism has not been clarified yet. In our department, all members are striving to develop computer simulation methods and models in order to clarify the mechanical behavior and function of the living tissues from nano-level in the cell to whole body under such dynamic environment.We welcome the participation of students who have creative curiosity and enthusiasm to research objects in coordination area among medicine, engineering and pharmaceutical sciences.

Research and EducationWe are doing both basic and applied research projects to assist the diagnosis/treatment for the functional regenerative medicine of the living body by means of computer science and biomaterial engineering in development of artificial organs which harmonize biomechanically with the living tissues. It is indispensable in the regenerative medicine for differentiation and proliferation of stem cells to useful cells/tissues/organs to develop the technology of the nano medical engineering such as proper stimulation control of the cell environment, and acquisition and analysis of answer signals of the cells.It is important to assure the biomechanical compatibility between artificial organs and the periphery living tissues. If the biomechanical compatibility is not good, re-operation becomes needed due to adaptational transformation such as contraction/absorption of the living issues. Accordingly, it is necessary to know the mechanical characteristics of the living tissues first of all, however, it has been difficult to measure in situ condition by the conventional engineering method, although. Thereupon, we are tackling with the development of the original methods that measures the dynamic characteristics and functions of the living body invasively. On the basis of the information that was obtained by our novel methods with sound wave and MRI etc, computer simulations are utilized to examine and predict what influences of external forces on the living body under dynamic environment.Furthermore, for the regeneration of the living tissue functions, we are developing many kinds of implants with high safe functions made of polymeric, ceramic and metallic materials. Combinations of artificial materials and living tissues enables design/manufacturing of implants variously in shapes and functions. In our department, for instance, a hybrid type dental implants with regeneration of periodontal ligaments has been developed, and also, various biodegradable materials, which should be resorbed after their mission in the living body, have been produced.

Recent Publications1. Matsumura, K., Bae ,J-Y., Hyon, S-H. : Polyampholytes as cryoprotective agents for mammalian

cell cryopreservation.Cell Transplant. Vol.19 691-699 (2010) 2. Nakai R, Azuma T, Kishimoto T, Hirata T, Takizawa O, Hyon SH, Tsutsumi S:Development of

a high-precision image-processing automatic measurement system for MRI visceral fat images acquired using a binomial RF-excitation pulse. Magnetic Resonance Imaging.28(4):520-6 (2010)

3. Kazuaki Matsumura, _Suong-Hyu Hyon_. : Polyampholytes as low toxic efficient cryoprotective agents with antifreeze protein properties.Biomaterials 30.4842-4849 (2009)

4. Azuma T, Nakai R, Takizawa O, Tsutsumi S: In vivo structural analysis of articular cartilage using diffusion tensor MRI. Magnetic Resonance Imaging.27(9):1242-1248 (2009)

❶ Effective cryopreservation of human iPS cell ❷ New cryoprotectant (no frozenpolyamino

acid) ❸ New medical adhesive of two liquid reactive

type that has biodegradability ❹ MRI device for research of MFS (1.5T) ❺ Rat MR imaging data ❻ Result of analysis of fMRI

Medical Simulation Engineering Research Center for Nano Medical Engineering Institute for Frontier Medical SciencesAssociate Professor : Suong-Hyu Hyon TEL : +81-75-751-4125 FAX : +81-75-751-4125 URL : http://www.frontier.kyoto-u.ac.jp/

bf04/index.html

Medical Simulation Engineering Research Center for Nano Medical Engineering

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The research projects carried out in this laboratory are concerned with post-translational events in the expression of genetic information. Specifically, processes of protein translocation across and integration into the membrane, membrane protein proteolysis and extracytoplasmic stress responses are investigated by combined molecular genetic, biochemical and structural approaches.Second group is studying the lifecycle of human papillomavirus (HPV) and the molecular mechanism of the virus-induced tumor formation. The interaction between HIV and host immune cells is also under investigation.Third group is studying the regulatory mechanism of Wnt/beta-catenin pathway and its role on cell biology.

Yoshinori Akiyama, D. SciProfessor

Research and EducationStudy of prote in t ranslocat ion machinery: Translocation of newly synthesized non-cytoplasmic proteins across the membrane is mediated by the evolutionary conserved SecYEG complex and the motor protein SecA in E. coli. We are studying the dynamic interactions and structural changes of these Sec proteins to elucidate the molecular mechanism of the protein translocation.

Proteolysis plays important roles not only in quality control but also in functional regulation of membrane proteins. We are interested in both of these aspects. Also we address the problem of how an E coli cell responds to the “membrane stresses” caused by accumulation of potentially deleterious abnormal membrane proteins.

HPV infection and the tumorigenesis: HPV is an etiological agent for benign tumors at epithelial organ, such as warts and condylomas. The infection of HPV has been recognized as a major risk factor for cervical cancer. The viral life-cycle is strictly governed by the differentiation program of the host cell, and the cross-talk between the virus and the host cell is an unique feature of HPV biology.

Regulatory mechanism of Wnt/beta-catenin pathway: Wnt signaling is an essential component of development process and carcinogenesis. We identified casein kinase Ialpha as a priming kinase for the phosphorylation of beta-catenin/Arm, which was critical for the regulation of beta-catenin/Arm degradation. We are further investigating the regulatory mechanisms of the signaling pathway and trying to establish the integration in a variety of biological aspects.

Recent Publications1. Akiyama, Y. (2009) Quality control of cytoplasmic membrane proteins in Escherichia coli. J.

Biochem. 46, 449-54 2. Tsukazaki, T.,* Mori, H.,* Fukai, S., Ishitani, R., Mori, T., Dohmae, N., Perederina, A., Sugita, Y.,

Vassylyev, D. G., Ito, K. and Nureki O. (2008) Conformational transition of Sec machinery inferred from bacterial SecYE structures. Nature 455, 988-991. * These authors contributed equally to this work.

3. Koide, K., Ito. K., and Akiyama, Y. (2008) Substrate recognition and binding by RseP, an Escherichia coli intramembrane protease. J. Biol. Chem. 283, 9562-9570.

4. Yoshida, H., Kajitani, N., Satsuka, A., Nakamura, H. and Sakai, H. (2008) Ras modifies proliferation and invasiveness of cells expressing human papillomavirus oncoproteins. J. Virol. 81, 8820-8827

5. Matsubayashi, H., Sese, S., Lee, J.S., Shirakawa, T., Iwatsubo, T., Tomita, T. and Yanagawa, S. (2004) Biochemical characterization of the Drosophila wingless signaling pathway based on RNA interference. Mol Cell Biol. 24, 2012-2024

❶ Translocation/integration, folding, and degradation of the E. coli cell surface proteins and cellular responses to membrane stresses.

❷ Crystal structure of T. Thermophilus SecA protein ❸ Ras activation conferred invasion potential to keratinocytes expressing high-risk type E7. ❹ Disruption of Casein kinase Ialpha (CKIalpha) by RNAi induces a naked cuticle in the

Drosophila embryo.

Gene AnalysisInstitute for Virus ResearchProfessor : Yoshinori Akiyama Associate Professor : Hiroyuki Sakai, Hiroyuki Mori Assistant Professor : Shin-ichi Yanagawa, Shin-ichiro Narita TEL : +81-75-751-4040 FAX : +81-75-771-5699 e-mail : [email protected] URL : http://www.virus.kyoto-u.ac.jp/Lab/

akiyama/index.html

Gene Analysis

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- Institute for Virus Research


The universe of antigens recognized by the immune system has recently been expanded to include not only protein antigens but also lipid antigens. The Lipid-specific T cell response is mediated primarily by a novel lineage of antigen-presenting molecules, CD1, that exhibits an outstanding ability to bind lipid antigens and present them to specific T cells. By orchestrating immunological, cell biological, and biochemical approaches, our laboratory aims to establish the molecular and cellular basis for lipid antigen presentation and T cell activation, hoping to contribute to accurate diagnosis of cancer and microbial infection and develop a new type of lipid-based vaccines. We encourage young investigators interested in our research endeavors to join us regardless of their educational backgrounds.

Masahiko Sugita, M.D., Ph.D.Professor

Research and EducationRapid progress in molecular biology in the 1980s resulted in elucidation of a molecular basis for the protein antigen-specific immunity. Milestone discoveries such as X-ray crystal lographic visualization of peptide-MHC interactions and the diversity of T-cell receptors generated by gene rearrangement convinced most immunologists with excitement that the molecular basis for “antigen specificity”, a most salient feature of our immune system, had been fully disclosed. While sharing excitement as one among members of the immunology community, I was personally puzzled by a naive question that came up to me after clinical practice. “Does the universe of antigens recognized by the immune system only include proteins?” Glycan-specific immune responses are elicited following pneumococcal infection. Campylobacter infection often induces immune responses directed against glycolipids. Autoantibodies against double-strand DNA are detected in patients with systemic lupus erythematosus. These clinical observations provide evidence for the yet unappreciated ability of the immune system to specifically recognize non-protein antigens that include sugars, lipids, and nucleic acids. Our laboratory now aims to unravel a molecular and cellular basis for the lipid-specific immune response and to develop lipid-based vaccines against cancer and microbial infection. Young investigators sharing enthusiasm with us would join in our journey to these goals.

Recent Publications1. Nakao, H., et al. (2009) Mycolyltransferase from Mycobacterium leprae excludes mycolate-

containing glycolipid substrates. J. Biochem. 146:659-665. 2. Otsuka, A., et al. (2008) Trehalose dimycolate elicits eosinophilic skin hypersensitivity in

mycobacteria-infected guinea pigs. J. Immunol. 181:8528-8533. 3. Matsunaga, I., et al. (2008) Mycoyltransferase-mediated glycolipid exchange in Mycobacteria. J.

Biol. Chem. 283: 28835-28841. 4. Matsumoto, Y., et al. (2008) Guillain-Barre syndrome-associated IgG responses to gangliosides are

generated independently of CD1 function in mce. J. Immunol. 181: 39-43. 5. Hava, DL., et al. (2008) Evasion of peptide, but not lipid antigen presentation, through pathogen-

induced dendritic cell maturation. Proc. Natl. Acad. Sci. USA. 105: 11281-11286.

❶ In contrast to MHC molecules that present protein antigens to T cells, CD1 molecules bind lipid antigens and present them to T cells. These two pathways function cooperatively to support host defense.

❷ E l e c t r o n m i c r o g r a p h s o f dendritic cells (left) that primarily function to mediate lipid antigen presentat ion and dendr i t ic cell lysosomes (right) where lipid antigen loading onto CD1 molecules occurs.

❸ Guinea pigs used for our study of CD1 (upper panel) and CD1-positive cells in CD1 transgenic mice (lower panel, stained in brown).

❹ A group photo of our laboratory

Cell RegulationInstitute for Virus ResearchProfessor : Masahiko Sugita Associate Professor : Isamu Matsunaga TEL : +81-75-751-4028 FAX : +81-75-752-3232 e-mail : [email protected] URL : http://www.virus.kyoto-u.ac.jp/Lab/

SugitaLab.html

Cell Regulation Viral Oncology

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Life is characterized by the interaction of individuals with their surroundings, including pathogens such as viruses. Upon infection, viruses interfere with normal cellular function to create an environment amenable to viral replication and the production of infectious particles, but hosts have evolved mechanisms to inhibit the spread of infection. Clarification of the molecular mechanisms of anti-viral pathways will facilitate our understanding of host resistance as well as inform our knowledge of normal cellular physiology. Additionally, viral infection is known to give rise to multiple pathological states including cancer, and increased knowledge of anti-viral defense could lead to prevention of viral related diseases. We welcome candidates who are enthusiastic to investigate this growing and important field.

Keizo Tomonaga, D.V.M., Ph.DProfessor

Research and EducationDepending on the particular virus, infections can be subclinical or lead to systemic syndromes including cancer or death. There are at least six viruses known to cause cancer in humans, and they are referred to as oncogenic viruses. Using human T-cell leukemia virus and hepatitis C virus, we are investigating the mechanisms of viral replication in the hopes of developing useful anti-viral agents. Additionally, we wish to clarify the molecular mechanisms by which these viruses regulate cell proliferation. Some proteins of oncogenic viruses modulate cell proliferation, and an increased understanding of the mechanism of action of viral proteins could provide valuable insight into the normal physiology of cell proliferation. Through comparisons of cell proliferation in infected and uninfected cells, a comprehensive analysis of the characteristics of cell proliferation in these two states can be undertaken.

Recent Publications1. Honda T, Fujino K, Okuzaki D, Ohtaki N, Matsumoto Y, Horie M, Daito T, Itoh M and Tomonaga

K. Upregulation of insulin-like growth factor binding protein 3 in astrocytes of transgenic mice expressing Borna disease virus phosphoprotein. J. Virol. (in press)

2. Horie M, Honda T, Suzuki Y, Kobayashi Y, Daito T, Oshida T, Ikuta K, Jern P, Gojobori T, Coffin JM and Tomonaga K. Endogenous non-retroviral RNA virus elements in mammalian genomes. Nature 463:84-87 (2010)

3. Watanabe Y, Ohtaki N, Hayashi Y, Ikuta K and Tomonaga K. Autogenous translational regulation of the Borna disease virus negative control factor X from polycistronic mRNA using host RNA helicases. PLoS Pathog. 5:e1000654 (2009)

4. Aly HH, Qi Y, Atsuzawa K, Usuda N, Takada Y, Mizogami M Shimotohno K, Hijikata M. Strain-dependent viral dynamics and virus cell interactions observed in a novel in vitro system supporting the life cycle of blood borne HCV. Hepatology 50:689-696. (2009)

5. Miyanari Y, Atsuzawa K, Usuda N, Watashi K, Hishiki T, Zayas M, Bartenschlager R, Wakita T, Hijikata M, Shimotohno K. The lipid droplet is an important organelle for hepatitis C virus production. Nat. Cell Biol. 9:1089-1097. (2007)

❶ B o r n a d i s e a s e v i r u s pe rs i s t en t l y i n fec ted neuronal cells. Left and r ight panels show DIC and confocal microscope images, respec t ive ly. The virus-specif ic dot structures (green) are formed in the cell nucleus (blue).

❷ Reduction of Purkinje cell neurons in the cerebellum o f t r a n s g e n i c m i c e expressing Borna disease virus phosphoprotein in astrocytes.

❸ E lec t ron mic roscop ic observat ion of human T-cell leukemia virus.

❹ A putative image of HCV r e p l i c a t i o n c o m p l ex . HCV alters structure of ER membrane so that the virus establishes the replication complex shown here.

Human Tumor VirusesInstitute for Virus ResearchProfessor : Keizo Tomonaga Associate Professor : Makoto Hijikata TEL : +81-75-751-4046 FAX : +81-75-751-3998 e-mail : [email protected] URL : http://www.virus.kyoto-u.ac.jp/Lab/

hitogan2007/index.html

Human Tumor Viruses Department of Viral Oncology

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The immune system has acquired sophisticated control mechanisms as a result of evolution at the front line of the war between host and microorganism. Thus, the immune system is important not only as a self-defense mechanism against pathogenic microorganisms but also as an interesting research field full of unexpected findings. Our laboratory aims to find new principles that are universal to medicine and biology. Therefore, we welcome young students with much enthusiasm and interest in immunology.

Koichi Ikuta, M.D., Ph.D.Professor

Research and EducationThe immune system has adopted the strategy “Learn oneself, and then learn the enemy” to fight against pathogenic microorganisms. The step “Learn oneself” is the stage of development and differentiation of immune cells. This stage includes important questions such as the decision of cell destiny and the control of lymphocyte differentiation. Our themes mainly reside in these fields, which are full of unsolved questions. Our laboratory has made two major achievements. F i r s t , we have found tha t f e ta l and adu l t h e m a t o p o i e t i c s t e m c e l l s h a v e d i f f e r e n t developmental potential to differentiate into lymphocytes. Second, we have demonstrated that interleukin-7 controls DNA recombination of lymphocyte antigen receptor genes by changing chromatin structure. Both of them are related with fundamental questions in medicine and biology. Based on these findings, we are now pursuing research on development of the immune system and regulation of immune response, focusing on the following questions: (1) molecular mechanism of lineage decision of immune cells from hematopoietic stem cells; (2) control mechanism of lymphocyte antigen receptor genes by chromatin structural changes; (3) regulation of immune response by controlling cytokine receptor expression; (4) distribution and function of IL-7-producing cells. In our laboratory, every graduate student will be involved in one of the projects and trained as to acquire the ability to plan, accomplish and publish one’s work. In the process, one will acquire the skills on flow cytometry, cell sorting, organ culture, transgenic and knockout mice as well as general techniques on molecular biology, cell biology, and immunology.

Recent Publications1. Ye SK, Maki K, Kitamura T, Sunaga S, Akashi K, Domen J, Weissman IL, Honjo T, Ikuta K (1999):

Induction of germline transcription in the gamma locus by Stat5: implications for accessibility control by the IL-7 receptor. Immunity, 11:213-223.

2. Ye SK, Agata Y, Lee HC, Kurooka H, Kitamura T, Shimizu A, Honjo T, Ikuta K (2001): The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation. Immunity, 15:813-823.

3. Lee HC, Ye SK, Honjo T, Ikuta K (2001): Induction of germline �transcription in the human T cell receptor gamma locus by STAT5. J. Immunol., 167:320-326.

4. Lee HC, Shibata H, Ogawa S, Maki K, Ikuta K. (2005): Transcriptional regulation of the mouse IL-7 receptor alpha promoter by glucocorticoid receptor. J. Immunol., 174:7800-7806.

5. Maki, K., Ikuta, K. (2008): MEK1/2 induces STAT5-mediated germline transcription of the TCRgamma locus in response to IL-7R signaling. J. Immunol., 181:494-502.

❶ gamma/deltaT cells (red) and dendritic cells (green) in the epithelium of wild-type mouse skin. IL-7 receptor knockout mice lack gamma/deltaT cells.

❷ IL-7 receptor knockout mice lack gamma/deltaT cells in the epithelium of small intestine.

❸ S ta t5 , ac t i va ted by IL -7 receptor, binds to the T cell antigen receptor gamma-chain locus, changes i ts c h r o m a t i n s t r u c t u r e by h is tone acety la t ion , and induces transcr iption and recombination.


Biological Protection Institute for Virus ResearchProfessor : Koichi Ikuta Assistant Professor : Masamichi Ueda, Shizue Tani-ichi, Takahiro Hara TEL : +81-75-751-4012 FAX : +81-75-751-4810 e-mail : [email protected] URL : http://www.virus.kyoto-u.ac.jp/Lab/

ikuta.html

Biological Protection Department of Biological Responses

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We investigate the molecular mechanism of thioredoxin binding protein-2 (TBP-2)/ Txnip and alpha-arrestin proteins which attract much attention as multifunctional regulators in the pathogenesis of diseases including cancer and Diabetes Mellitus. We perform multidimensional approaches such as analyses of knockout mice and multiomics, in tight collaborations with researchers in clinical departments. Our goal is to elucidate the pathogenesis of these diseases and develop approaches against these diseases.

Research and Education We investigate the molecular mechanism of thioredoxin binding protein-2 (TBP-2/Txnip) and alpha-arrestin family proteins, to elucidate the pathogenesis of and to develop approaches against Diabetes Mellitus, cancer, and viral infection.Main research projects are 1. Study of the mechanism TBP-2/ Txnip for Diabetes Mellitus, cancer, and viral infection. We showed that TBP-2 is an important molecule in the pathogenesis of Diabetes Mellitus. TBP-2 regulates the secretion of insulin, sensitivity of insulin and apoptosis. We also revealed that TBP-2 regulates the transcription of important metabolic regulatory genes through the control of co-activators. We are now investigating the molecular mechanism of TBP-2 in order to develop new approaches against Diabetes Mellitus.TBP-2 also plays important roles in cancer suppression and the regulation of inflammatory response. We are studying the molecular mechanism. 2. Study of TLIMP/ ARRDC3, an alpha-arrestin protein in the regulation of receptor endocytosis. TBP-2-like inducible membrane protein (TLIMP)/ arrestin domain containing protein 3 (ARRDC3) regulates the endocytosis of receptors such as the beta2-adrenagic receptor. Since TLIMP/ ARRDC3 may act as an adaptor/ scaffold to regulate endocytotic process and signals of various receptors, we are studying the molecular function of TLIMP/ARRDC3. 3. Study of redox and oxidative stress signaling. We are investigating redox and oxidative stress signaling by analyzing molecular functions of thioredoxin family proteins.

We use multidimensional approaches, connecting structural analyses, proteome and transcriptome analyses, biochemical and physiological approaches and analyses in pathophysiology, in a tight collaboration with clinical departments. We educate graduate students based on their own motivations and interests. Graduate students with various backgrounds gather in our laboratory. We welcome the visit of young investigators.

Recent Publications1. Yoshihara, E., Fujimoto, S., Inagaki, N., Okawa, K., Masaki, S., Yodoi, J., Masutani, H. (2010)

Disruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity. Nat Commun., 1:127.

2. Chen, Z., Lopez-Ramos, DA., Yoshihara, E., Maeda, Y., Masutani, H., Sugie, K., Maeda, M., Yodoi, J. (2010) Thioredoxin-binding protein-2 (TBP-2/VDUP1/TXNIP) regulates T-cell sensitivity to glucocorticoid during HTLV-I-induced transformation. Leukemia.

3. Mochizuki, M., Kwon, YW., Yodoi, J., Masutani H. (2009) Thioredoxin regulates cell cycle via the ERK1/2-cyclin D1 pathway. Antioxid Redox Signal. 11, 2957-2971.

4. *Oka, S., *Yoshihara, E., Bizen-Abe, A., Liu, W., Watanabe, M., Yodoi, J., Masutani, H. (2009) Thioredoxin binding protein-2/thioredoxin-interacting protein is a critical regulator of insulin secretion and peroxisome proliferator-activated receptor function. Endocrinology. 150, 1225-1234. * These authors contributed equally to this work.

❶ M u l t i p l e B i o l o g i c a l R o l e s o f Thioredoxin Binding Protein-2 (TBP-2)/ Txnip and alpha-Arrestin Family Proteins. TBP-2/Txnip is involved in various diseases such as Diabetes Mellitus, hyperlipidemia, Cancer and inflammatory disorders.

❷ Improvement of hyperglycemia by disruption of TBP-2 in ob/ob mice, a genetic animal model of human obesity and type 2 Diabetes Mellitus. Disruption of TBP-2 did not change obesity (left, and right upper figure) but improved hyperglycemia (right lower).

❸ Regulation of receptor endocytosis by TBP-2-like Inducible Membrane Protein (TLIMP)/ Arrestin Domain Containing 3 protein (ARRDC3). T L I M P / A R R D C 3 r e g u l a t e s e n d o c y t o s i s , u b i q u i t i n a t i o n , degradation, and signal transduction of receptors. TLIMP/ ARRDC3 is located in inner membrane, endosomes and lysosomes (left lower).

Infection and Prevention Institute for Virus ResearchAssociate Professor : Hiroshi Masutani TEL : +81-75-751-4026, 4025 FAX : +81-75-761-5766 e-mail : [email protected] URL : http://www.virus.kyoto-u.ac.jp/virus/

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Infection and Prevention Biological Responses

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It is really fascinating and exciting to see the process where a fertilized egg develops into a complicated embryo. How does each cell in embryos know its own position and role? How do many events proceed coordinately at the right time and the right place? Many things remain to be solved in developmental biology. We are challenging these difficult but fascinating problems of developmental biology. The results from this research will be useful for the future regeneration therapy. We hope many students will join us to challenge these problems.

Ryoichiro Kageyama, M.D., Ph.D.Professor

Research and EducationThe research interest of this laboratory is to understand the molecular mechanism of cell differentiation and organogenesis. Particularly, we are interested in transcription factors that regulate neural development. Our research strategies are misexpressing the genes with retrovirus and electroporation (gain-of-function study) and generating knock-out mice (loss-of-function study). We are focusing on basic helix-loop-helix (bHLH) transcription factors such as the repressor-type bHLH factors Hes1 and Hes5 and the activator-type bHLH factors Math, Mash, NeuroD and Neurogenin. During neural development, the following three major steps occur sequentially: (1) maintenance of neural stem cells, (2) neurogenesis and (3) gliogenesis. We have demonstrated that the steps (1) and (3) are regulated by the repressor-type bHLH factors while the step (2) is regulated by the activator-type bHLH factors. These findings will be useful for the future regeneration therapy.We are also interested in biological clocks that regulate embryogenesis. We have recently found that the bHLH factors Hes1 and Hes7 act as two-hour cycle biological clocks in embryos. Hes7 regulates the timing of somite segmentation, which occurs every two hours in mice. We are now studying what developmental processes, besides somite segmentation, these biological clocks regulate. This research will open the new field “Developmental Chronobiology”.Regarding education, we are committed to providing graduate students with the highest quality of research environment and thereby educating them to be the scientists who play an essential role in international societies. Students with various backgrounds study Developmental Biology from the beginning and join the research project described above. They have the opportunity to present and discuss their results in domestic and international meetings and to publish them in international journals.

Recent Publications1. Kobayashi, T., Mizuno, H., Imayoshi, I., Furusawa, C., Shirahige, K., and Kageyama, R. (2009)

The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells. Genes & Dev. 23, 1870-1875.

2. Kageyama, R., Ohtsuka, T., Shimojo, H., and Imayoshi, I. (2008) Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition. Nature Neurosci. 11, 1247-1251.

3. Imayoshi, I., Sakamoto, M., Ohtsuka, T., Takao, K., Miyakawa, T., Yamaguchi, M., Mori, K., Ikeda, T., Itohara, S., and Kageyama, R. (2008) Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nature Neurosci. 11, 1153-1161.

4. Shimojo, H., Ohtsuka, T., and Kageyama, R. (2008) Oscillations in Notch signaling regulate maintenance of neural progenitors. Neuron 58, 52-64.

5. Niwa, Y., Masamizu, Y., Liu, T., Nakayama, R., Deng, C.-X., and Kageyama, R. (2007) The initiation and propagation of Hes7 oscillation are cooperatively regulated by Fgf and Notch signaling in the somite segmentation clock. Dev. Cell 13, 298-304.

❶ bHLH factors regulate three steps of neural development.

❷ The repressor - type bHLH factors Hes1 and Hes5 are essent ia l for maintenance of neural stem cells. (Upper) In the absence of Hes1 and Hes5, neurons are prematurely differentiated and neural stem ce l l s a re no t ma in ta ined . (Lower) Hes1;Hes5 double-null neural stem cells do not grow well and form only small neurospheres.

❸ Hes1 and Hes7 as two-hour cycle biological clocks. Hes1 and Hes7 expression oscillates autonomously by negat ive feedback. These biological clocks regulate the progress of embryogenesis.

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Growth Regulation Institute for Virus ResearchProfessor : Ryoichiro Kageyama Associate Professor : Toshiyuki Ohtsuka Assistant Professor : Taeko Kobayashi TEL : +81-75-751-4011 FAX : +81-75-751-4807 e-mail : [email protected] URL : http://www.virus.kyoto-u.ac.jp/Lab/

toppage.zoushoku.kageyama.html

Growth Regulation Department of Cell Biology

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Human immunodeficiency virus (HIV) is a causative agent for acquired immunodeficiency syndrome (AIDS). After the discovery of HIV, it has been well known that ‘‘retroviruses can cause some human diseases’’. We now know the importance of retrovirus research. The isolation of human retroviruses was the 5th major discovery and provided paradigm shift on history of Retrovirology. The 1st~4th major discoveries are as follows; (1) the isolation of a pathogenic retrovirus, (2) the development of the focus assay for oncogenic retrovirus, (3) the discovery of reverse transcriptase, (4) the derivation of retroviral oncogene from cellular genomes. It is clear that these discoveries provided strong advances not only on Virology itself but also general Cell Biology. Information on Molecular Biology has been obtained from these retrovirus researches. Therefore, we believe that our efforts will contribute to Medical as well as Life Sciences. Yoshio Koyanagi, M.D., Ph.D.

Professor

Research and EducationResearch projects have been arranged for graduate students and they should join in international scientific fields.1) Replication of viral genomeVirus infects cell and replicates. Viral genome moves from virion-produced cell to adjacent naive cells. This is a most significant characteristics of virus. The mechanism of this infection event is a primary theme. The genome movement is not restricted in cell to cell infection. Inside cells, viral genomes or/and viral proteins move. Virus uses cellular trafficking machinery. We wish to learn the mechanism. (Fig. 1. Entry steps of HIV)2) Regulation of HIV replication by immunological moleculesVirus cannot replicate without cells. However, we don’t know yet how many cellular factors virus requires for its replication. Since it has been finding many factors on HIV replication, we wish to learn the mechanism of HIV replication from aspect of Immunology and Virology.3) Mechanism of HIV pathogenesisHIV causes immunodef ic iency in human . The mechan ism of the immunodef ic iency remains unclear. It has been analyzing how the immunodeficiency occurs using in vitro-cell culture models and in vivo-animal models. We developed a mouse system that human immune system is transplanted in SCID mouse and in this human-chimera mouse abundant CD4 cell killing can be reproduced with HIV infection. 4) Development of retrovirus vector system for gene therapy and gene discoveryVirus transmits the gene into cells. It has been trying to take advantage of this viral nature for gene therapy in human disease. HIV-based retrovirus vector has promising properties to infect non-dividing cell and integrate in chromosome DNA. Purpose of this project is improvement of the vector system for practical use as well as discovery of gene functions.

Recent Publications1. Sato K, Aoki J, Misawa N, Daikoku E, Sano K, Koyanagi Y. (2008) Modulation of human

immunodeficiency virus type 1 infectivity through incorporation of tetraspanin Proteins. J. Virol. 82:1021-1033.

2. Kitayama H, Miura Y, Ando Y, Hoshino S, Ishizaka Y, Koyanagi Y. (2008) Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction J. Virol. 82:2528-2542.

3. Yoshida T, Kawano Y, Sato K, Ando Y, Aoki J, Miura Y, Komano J, Tanaka Y, Koyanagi Y. (2008) A CD63 mutant inhibits T-cell tropic HIV-1 entry by disrupting CXCR4 trafficking to the plasma membrane. Traffic 9, 540-558.

4. Sato K, Izumi T, Misawa N, Kobayashi T, Yamashita Y, Ohmichi M, Ito M, Takaori-Kondo A, Koyanagi Y. (2010) Remarkable lethal G-to-A mutations in vif-proficient HIV-1 provirus by individual APOBEC3 proteins in humanized mice. J. Virol. 84, 9546-9556.

5. Kobayashi T, Ode H, Yoshida T, Sato K, Gee P, Yamamoto SP, Ebina H, Strebel K, Sato, Koyanagi Y. (2011) Identification of amino acids in the human tetherin transmembrane domain responsible for HIV-1 Vpu interaction and susceptibility. J. Virol. 85, 932-945.

❶ Entry step of HIV. ❷ Humanized SCID mouse is susceptible

for HIV infection. ❸ cDNA library-expressing lentivirus can

be used to select genes that provide the resistance to HIV infection.

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Viral PathogenesisInstitute for Virus ResearchProfessor : Yoshio Koyanagi Assistant Professor : Hirotaka Ebina TEL : +81-75-751-4813 FAX : +81-75-751-4812 e-mail : [email protected] URL : http://www.virus.kyoto-u.ac.jp/Lab/

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Viral Pathogenesis Center for Human Retroviruses Research

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Human T-cell leukemia virus type I (HTLV-I), and human immunodeficiency virus (HIV) are two major human retroviruses. HTLV-I induces the clonal proliferation of infected cells by pleiotropic actions of viral proteins. After a long latent period, HTLV-I causes adult T-cell leukemia (ATL) and inflammatory diseases in a part of carriers. On the other hand, HIV destroys CD4 positive T-lymphocytes, and ruins the immune system of infected individuals, resulting in the onset of acquired immunodeficiency syndrome (AIDS). In our laboratory, we pursue the molecular mechanisms of caner, virus induced diseases through research of these human retroviruses.

Masao Matsuoka, M.D., Ph.D.Professor

Research and EducationOur goal is to clarify the molecular mechanisms of human retrovirus-associated diseases, adult T-cell leukemia (ATL) and AIDS, and establish the new therapeutic strategies against such diseases. In HTLV-I, we are studying the molecular mechanism of HTLV-I induced T-cell proliferation, inflammatory diseases, and leukemogenesis. We also challenge to establish the new strategy for treatment against ATL based on our research. We found that HTLV-I bZIP factor gene, which is encoded by the minus strand of HTLV-I, play an important role in its pathogenesis. We continue to study the molecular mechanism of HBZ gene in ATL.Highly active anti-retroviral therapy (HAART) dramatically changes the treatment to HIV-infected individuals, and improves their prognosis. However, the eradication of HIV is impossible even by HAART, and long-term administration of anti-HIV drugs induces resistant viruses in vivo. In our laboratory, we are developing the new anti-HIV drugs, and analyzing the mechanism of resistance against anti-HIV drugs.

Recent Publications1. Satou Y, Yasunaga J-I, Zhao T, Yoshida M, Miyazato P, Takai K, Shimizu K, Ohshima K, Green PL,

Ohkura N, Yamaguchi T, Ono M, Sakaguchi S, Matsuoka M. HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In Vivo. PLoS Pathog, 7: e1001274, 2011.

2. Fan J, Ma G, Nosaka K, Tanabe J, Satou Y, Koito A, Wain-Hobson S, Vartanian JP, Matsuoka M. APOBEC3G generates nonsense mutations in human T-cell leukemia virus type 1 proviral genomes in vivo. J Virol, 84: 7278-7287, 2010.

3. Matsuoka M, Jeang KT. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat Rev Cancer, 7: 270-280, 2007.

4. Tamaki H, Matsuoka M. Donor-derived adult T-cell leukemia after allogeneic bone marrow transplantation. N Eng J Med 354: 1758-1759, 2006.

5. Satou Y, Yasunaga J-I, Yoshida M, Matsuoka M. The HTLV- I bZIP factor gene mRNA supports proliferation of adult T-cell leukemia cells. Proc. Natl. Acad. Sci. USA, 103: 720-725, 2006.

❶ Morphology of adult T-cell leukemia cells. ATL cells with lobulated nuclei are called as “flower cells”.

❷ HBZ induces T-cell lymphoma and the inflammatory diseases in vivo.

❸ Regulatory T cells are increased in HBZ transgenic mice.

❹ Six-helix bundle formation between SC34EK (blue) and N-HR (N36; pink)

❺ Staff. Professor Matsuoka (left) and Instructor Yasunaga (right)

Viral InfectionsInstitute for Virus ResearchProfessor : Masao Matsuoka Instructor : Jun-ichiro Yasunaga TEL : +81-75-751-4048 FAX : +81-75-751-4049 e-mail : [email protected] URL : http://www.virus.kyoto-u.ac.jp/Lab/

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Viral Infections Center for Human Retroviruses Research

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Due to the lack of definitive prophylactic and therapeutic measures, viral infectious diseases, such as highly pathogenic avian influenza virus, hepatitis C and AIDS, are still major threats to humans. It is essential to elucidate the pathogenic mechanisms induced by virus infections to establish more effective prophylaxis and therapy. To this end, we have been developing animal models for AIDS and analyzing disease and pathogenic mechanisms using the models.

Tatsuhiko Igarashi, D.V.M. & Ph.D.Professor

Research and EducationOur laboratory has been developing, improving animal models for AIDS and analyzing the disease and pathogenic mechanisms using the models. The followings are our basic experimental techniques:•Modification of molecularly cloned viruses•Analysis of virus evolution through animal passage•Measurement of viral burden and lymphocyte subset•Assessment of humoral and cellular immune reaction against virusWe are also involved in histochemical analyses of virus-infected animals.Our educational goal is to develop an integrated view to host-parasite relationship at molecular, cellular, and organism level, employing knowledge and techniques of molecular biology, biochemistry, virology, immunology, pathophysiology and veterinary medicine. We wish to nurture “virologists” who can handle virus and analyze biological aspects of pathogenic viruses. While the progress of molecular biology has enabled us to “dissect” and analyze virus replication cycle more precisely and safely, it has made “virologists” seemingly less important. We think “virologists” are heavily needed under the current circumstance where infectious diseases keep emerging or re-emerging. We encourage motivated young scientists to join our research.

Recent Publications1. Igarashi, T., Iyengar, R., Byrum, R. A., Buckler-White, A., Dewar, R. L., Buckler, C. E., Lane, H.

C., Kamada, K., Adachi, A., and Martin, M. A. (2007b) Human immunodeficiency virus type 1 derivative with 7% simian immunodeficiency virus genetic content is able to establish infections in pig-tailed macaques. J. Virol., 81, 11549-11552.

2. Shimizu, Y., Inaba, K., Kaneyasu, K., Ibuki, K., Himeno, A., Okoba, M., Goto, Y., Hayami, M., Miura, T., and Haga, T. (2007) A genetically engineered live-attenuated simian-human immunodeficiency virus that co-expresses the RANTES gene improves the magnitude of cellular immunity in rhesus macaques. Virology, 361, 68-79.

3. Miyake, A., Ibuki, K., Enose, Y., Suzuki, H., Horiuchi, R., Motohara, M., Saito, N., Nakasone, T., Honda, M., Watanabe, T., et al. (2006) Rapid dissemination of a pathogenic simian/human immunodeficiency virus to systemic organs and active replication in lymphoid tissues following intrarectal infection. J. Gen. Virol., 87, 1311-1320.

4. Igarashi, T., Brown, C. R., Endo, Y., Buckler-White, A., Plishka, R., Bischofberger, N., Hirsch, V., and Martin, M. A. (2001) Macrophage are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4+ T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): Implications for HIV-1 infections of humans. Proc. Natl. Acad. Sci. U. S. A., 98, 658-663.

5. Igarashi, T., Brown, C., Azadegan, A., Haigwood, N., Dimitrov, D., Martin, M. A., and Shibata R. (1999) Human immunodeficiency virus type 1 neutralizing antibodies accelerate clearance of cell free virions from blood plasma. Nat. Med. 5(2): 211-216.

❶ Schematic representations of genomic organization of HIV-1, SIV, and SHIV and virus particle of SHIV.

❷ CD4+ T cell profi les of SHIV-infected animal (left, pre-infection, right, post infection, note the cel l population in the circle, credit, Y. Fukazawa)

❸ Virus-infected cells (brown) revea led in the sma l l intestine of SHIV-infected animal (Credit, K. Inaba)

❹ Lab members

Viral Pathogenicity Institute for Virus ResearchProfessor : Tatsuhiko Igarashi Associate Professor : Tomoyuki Miura Assistant Professor : Takeshi Kobayashi TEL : +81-75-751-3981 FAX : +81-75-761-9335 e-mail : [email protected] URL : http://www.virus.kyoto-u.ac.jp/Lab/

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Viral Pathogenicity Experimental Research Center for Infectious Diseases

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Radiation biology has recently come to attract attention as an investigational area contributing to elucidation of various heredity mechanism from classic study of conventional radiation influence. Especially, it is a topics that genetic effect by radiation exposure is propagated via spatial (bystander effects) and time distance (delayed effects). We are aiming to clarify the non-DNA target of hereditary influence by radiation and the mechanism to maintain gene homeostasis.

Masami Watanabe, Ph.D.Professor

Research and EducationAfter the life was born on the earth 3,600 million years ago, the life has not been separated from various environmental stress, such as radiation, temperature and pressure. And the life built cell structure to distinguish it from the surrounded environment. Recently, it has been made clear that a cell are using basic biological reaction mechanism for replying to various stress. Therefore, basic biological reaction may be clarified by discovering stress response mechanism. Dysfunction of stress response may be a cause of carcinogenesis and acceleration of aging. It is also expected that a disease is cured by fixing a stress response function normally. We choose four environmental stress factors, such as radiation, hyperthermia, oxygen and pressure, and are doing the study focused on the following topics along such a working hypothesis.(1) Mechanism of carcinogenesis and aging(2) Mechanism of stress response(3) Development of new cancer therapy by hyperthermia and radiation(4) A search of cancer and aging prevention natural materialOur investigational purpose is prevention and a treatment of cancer and aging.

Recent Publications1. Toyokuni H, Maruo A, Suzuki K, Watanabe M: The contribution of radiation-induced large

deletion of the genome to chromosomal instability. Radiat. Res. in press, 2008 2. Harada Tm, Kashino G., Suzuki K, Matsuda N, Kodama S, Watanabe M: Different involvement of

radical species in irradiated and bystander cells. Intern. J. Radiat. Biol, in press, 2008 3. Masunaga S, Keizo Tano K, Watanabe M, Kashino G, Suzuki M, Kinashi Y, Ono K, Nakamura

J: Evaluation of the potential of hexamethylenetetramine as a combined agent with gamma-ray irradiation and cisplatin treatment in vivo, compared with tirapazamine British Journal of Radiology, in press, 2008

4. Yamauchi M, Oka Y, Yamamoto M, Niimura K, Uchida M, Kodama S, Watanabe M, Sekine I, Yamashita S, Suzuki K: Growth of persistent foci of DNA damage checkpoint factors is essential for amplification of G1 checkpoint signaling. DNA Repair (Amst). 7(3): 405-417, 2008.

5. Hamamoto T, Suzuki K, Yamauchi M, Kodama S, Sasaki H, Watanabe M: p53 status-dependent sensitization of human tumour cells to hyperthermia by plant flavonol. Int J Hyperthermia. 24(5): 415-424, 2008.

❶ It has been believed that the first target of radiation carcinogenesis is DNA. However, this hypothesis is not yet proved for carcinogenesis from low-dose radiation

directly. We analyzed our results of research on malignant cell transformation by low-dose

radiation during the past 30 years and came to strongly believe that a main target of radiation carcinogenesis is not DNA, but the centrosome, which is a protein that constitute the chromosomal homeostasis maintenance mechanism.

If our results are correct, the “mutation theory of carcinogenesis" is wrong. We suggest a new hypothesis about radiation carcinogenesis, which we named the

“protein-target hypothesis,” or, alternatively, the “aneuploidy-cancer hypothesis.” Picture; Normal centrosome (left upper) and normal nuclear division (left lower), structural

change of centrosome (upper and lower of center) and abnormal nuclear division (upper and lower of right).

Radiation BiologyResearch Reactor InstituteProfessor : Masami Watanabe Associate Professor : Keizo Tano Assistant Professor : Genro Kashino TEL : +81-72-451-2391 FAX : +81-72-451-2628 e-mail : [email protected] URL : http://www.rri.kyoto-u.ac.jp/rb-rri/rb-

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Radiation Biology Division of Radiation Life Science

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Kyoto University has 5 MW nuclear reactor for research at Kumatori in Osaka. A heavy water facility is attached to the reactor, and use of thermal and epithermal neutrons is available for researches of medicine and biology. Among them, development of boron neutron capture therapy (BNCT) for malignant tumors is most important and attractive subject. B-10 atom absorbs thermal neutron and emits high LET alpha particle. So, if B-10 accumulates in tumors selectively, only the tumor can be destroyed. In our country and also in the world, most patients have been treated in my reactor by our research group. Furthermore, development research of accelerator to generate neutrons for BNCT is also advanced, and the performance of clinical trial possible is realized. We welcome young researchers who aim both clinical and basic researches for BNCT. at much higher probability compared with other elements like as nitrogen, with shorter track than cancer cell diameter. Koji Ono, MD.PhD

Professor

Research and Education■ Radiation and Tumor Biology Research for BNCTThe range of the particles emitted through the reaction of B-10 nucleus and thermal neutron does not exceed the diameter of a cancer cell. On the other hand, the sell killing effect of thermal neutron itself is quite small. Moreover, capture probability of neutron with B-10 nucleus is extraordinarily large compared with reactions with other element nucleus in human body. Therefore, if B-10 compound accumulates in cancer cell or cancer tissue selectively, selective destruction and treatment of cancer cell or cancer is achievable. For liver cancer with multiple lesions we succeeded to accumulate B-10 compound at very high concentration and selectivity by using the technology of IVR. And by our original procedure, BNCT of liver cancer was performed first in the world. It is impossible to deliver curative radiation dose to the malignant pleural mesothelioma (MPM) which takes very complicated three dimensional lesions by X-ray irradiation technology avoiding lung tissue which adjoined intricately. Amino acid analogue involving B-10, BPA, accumulates in MPM pretty selectively through increased amino acid metabolism. When the effect was examined by the pleura dissemination model of cancer cells in rat, large extension of the survival time was obtained only by the BNCT group, and BNCT for MPM patient was carried out first in the world. Thus, basic research and clinical study are linked tightly and directly, and research is advanced.■ Physical and Engineering Research for BNCTThe neutron for BNCT has a fault with poor penetration into the deep part of body.In order to overcome this, the ideas of air injection to a postoperative dead space and shielding of the central part of the neutron exposure field was devised, and they have been applied to clinical BNCT. The performance of accelerator to generate neutrons for BNCT first in the world has reached the level in which a clinical trial is possible, and it is noted that neutron distribution of the accelerator is superior to a reactor neutron.

Recent Publications1. Minoru Suzuki, KazuoEndo, Hiroaki Satoh, Yoshinori Sakurai, Hiroaki Kumada, Hiroyuki

Kimura, Shinichiro Masunaga, Yuko Kinashi, Kenji Nagata, Akira Maruhashi, Koji Ono, "A novel concept of treatment of diffuse or multiple pleural tumors by boron neutron capture therapy (BNCT)", Radiotherapy and Oncology 88 (2008) 192-19

2. M. Suzuki, H. Tanaka, Y. Sakurai, G. Kashino,Y. Liu, S. Masunaga, Y. Kinashi, T. Mitsumoto, S. Yajima, H. Tsutsui, T. Sato, A. Maruhashi, K. Ono, “Impact of accelerator-based boron neutron capture therapy (AB-BNCT) on the treatment of multiple liver tumors and malignant pleural mesothelioma”, Radiotherapy and Oncology 92(2009)89-95

3. H.Tanaka, Y.Sakurai, M.Suzuki, S.Masunaga, Y.Kinashi, G.Kashino, Y.Liu, T.Mitsumoto, S.Yajima, H.Tsutsui, A.Maruhashi, K.Ono, "Characteristics comparison between a cyclotron-based neutron source and KUR-HWNIF for boron neutron capture therapy",Nuclear Instruments and Methods in Physics Research B 267 (2009) 1970–1977

4. G.ASHINO, S. FUKUTANI, M. SUZUKI, Y. LIU, K. NAGATA, S. MASUNAGA, A. MARUHASHI, H. TANAKA, Y. SAKURAI, Y. KINASHI, N. FUJII and K. ONO, “A Simple and Rapid Method for Measurement of10B-para-Boronophenylalanine in the Blood forBoron Neutron Capture Therapy UsingFluorescence Spectrophotometry” Journal of Radiation Research 50 (2009) 377-382

Particle Radiation OncologyResearch Reactor InstituteProfessor : Koji Ono Associate Professor : Shin-ichiro Masunaga Assistant Professor : Yong Liu·Natsuko Kondo TEL : 072-451-2575 FAX : 072-451-2627 e-mail : [email protected]

Particle Radiation Oncology Particle Radiation Oncology Research Center

- Research Reactor Institute


Infection is the war between the pathogen and its host. It is important to understand the nature of the both sides to prevent and treat the infection. Pathogenic bacteriology is the study on the bacterial pathogen and it is not very simple. The habitat of most bacterial pathogens is not humans but the natural environment. Knowledge and techniques of various fields are needed to understand how the pathogenic bacteria distinguish the natural environment and humans and how they act in the different environments. Some infections are spread across the international borders and international collaboration among the researchers is imperative to study the epidemiology.

Mitsuaki Nishibuchi, Ph.D.Professor

Research and EducationWe carry out comprehensive studies on the enteric infections caused by the pathogens such as Vibrio cholerae, Vibrio parahaemolyticus, and diarrheagenic Escherichia coli in our department. These infections are important, in particular, in Southeast Asia and isolation of the pathogens from the environment and the patients in collaboration with the workers in this area is the first step of the study. We not only identify the isolated bacterium but also, if needed, distinguish whether the isolates are pathogenic or nonpathogenic strains and examine for special characteristics (the serotype, phage type, genotype, etc.)We analyze the isolated strains not only for phenotypic characteristics but for their DNA fingerprints to investigate whether a particular strain in the environment is responsible for the infection or the infection is spread across the international borders.It is also important to study how the pathogenic strains distinguish the signals in the natural environment and the host and then express their virulence properties. To study this, we first identify the major virulence factor and the gene encoding this factor and then detect related genes and elucidate the mechanism regulating their expressions. We propose a working hypothesis from the results. The strains collected as above are very important property to examine the universality of the working hypothesis.We carry out the experiments and samplings by using the techniques associated with the environmental microbiology, clinical microbiology, molecular genetics, physiology, and immunology.

Recent Publications1. Nakaguchi, Y., and M. Nishibuchi. 2005. The promoter region rather than its downstream inverted

repeat sequence is responsible for low-level transcription of the thermostable direct hemolysin-related hemolysin (trh) gene of Vibrio parahaemolyticus. J. Bacteriol. 187(5):1849-1855.

2. Koitabashi, T., V. Vuddhakul, S. Radu, T. Morigaki, N. Asai, Y. Nakaguchi, and M. Nishibuchi. 2006. Genetic characterization of Escherichia coli O157:H7/- strains carrying the stx2 gene but not producing Shiga toxin 2. Microbiol. Immunol. 50(2): 135-148.

3. Koitabashi, T., S. Cui, K. Muhammad, and M. Nishibuchi. 2008. Isolation and characterization of the Shiga toxin gene (stx)-bearing Escherichia coli O157 and non-O157 from retail meats in Shandong Province, China and characterization of the O157-derived stx2 phages. J. Food Prot. 71(4):706-713.

❶ The research team in Malaysia that collaborated in isolation of Escherichia coli O157 ❷ We revealed that the Kanagawa phenomenon to detect pathogenic strains of Vibrio

parahaemolyticus (left) is not observed if a specific one-base change occurs in the tdh promoter.

❸ The DNA fingerprinting analysis that led to the discovery of the first pandemic spread of Vibrio parahaemolyticus infection. The newly emerged pandemic strains in the left panel showed a fingerprint that differed from those of the other strains.


Pathogenic MicrobiologyCenter for Southeast Asian StudiesProfessor : Mitsuaki Nishibuchi TEL : +81-75-753-4442 FAX : +81-75-753-7350 e-mail : [email protected] URL : http://www.cseas.kyoto-u.ac.jp/

Pathogenic Microbiology Division of Integrated Area Studies

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Modern clinical (bed-side) medicine have much succeeded in the lifesaving of the patients with acute diseases. As the results now, aging population have developed not only developed countries but also developing countries. However, modern clinical medicine in the hospital cannot completely deal with community-dwelling frail elderly patients with several chronic conditions living in each different ecology and socio-economical situation. Field medicine is addressing the comprehensive geriatric issues of community-dwelling elderly in the world using comprehensive geriatric assessment through actual medical field works.

Kozo Matsubayashi, M.D., Ph.D.Professor

Research and EducationWorking issues of our field medical teams are below.

(1) Comprehensive geriatric assessment and community-based intervention for the community-dwelling elderly in Japan.Comprehens ive ge r i a t r i c a s s e s smen t and community-based intervention for the community-dwelling elderly have been carried out in Kahoku and Tosa in Kochi, Sonobe in Kyoto, Yogo in Shiga and Urausu in Hokkaido.

(2) Comprehensive geriatric assessment for the community-dwelling elderly in Asia.Cross-sectional comprehensive geriatric assessment for the community-dwelling elderly have been carried out in Korea, West Java in Indonesia, Vietnam, Laos and Myanmar.

(3) Medical research for nerurodegenerative diseases in West Papua.We have carried out medical field research f o r a m y o t r o p h i c l a t e r a l s c l e r o s i s a n d Parkinson·Demantia complex disease in West Papua (Irianjaya) in Indonesia detecting some above patients. Future study is needed for etiological assessment.

Recent Publications1. Matsubayashi K et al. Mood Disorders in the Community-Dwelling Elderly in Asia. J Am Geriatr

Soc, 58 (1);213-214, 2010. 2. Matsubayashi K et al. ,Changing attitudes of elderly Japanese toward disease. J Am Geriatr Soc.

57 (9), 1732-1733, 2009. 3. Kimura Y et al. Comprehensive geriatric assessment of elderly highlanders in Qinghai, China IV:

Comparison of food diversity and its relation to health of Han and Tibetan elderly. Geriatr Gerontol Int 9 (4):359-365, 2009.

4. Okumiya K et al. Improvement in obesity and glucose tolerance in elderly people after lifestyle exchange 1 year after an oral glucose tolenrance test in a rural area in LAO People’s Democratic Republic. J Am Geriatr Soc 56: 1582-1583, 2008.

5. Fujisawa M et al. Trends in diabetes. Lancet 369:1257, 2007

❶ A scene of CGA in West Java in Indonesia. ❷ Home visit patients living in a house on the tree, in West Papua.

Field MedicineCenter for Southeast Asian StudiesProfessor : Kozo Matsubayashi TEL : +81-75-753-7368 FAX : +81-75-753-7168 e-mail : [email protected] URL : http://www.cseas.kyoto-u.ac.jp/

Field Medicine Division of Humans and the Environment

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The generation of induced Pluripotent Stem (iPS) cells with four defined transcription factors has led to the expectation that we will be able to better understand various pathologies, and discover new drugs by using cells obtained from patients, and thereby be able to carry out successful medical transplantation. However, before this new treatment modality can be clinically applied, strict evaluations must be performed while always maintaining patient safety as the first priority. To this end, we have tried to identify the optimal reprogramming factors, while continually improving the methods for iPS cell generation, and also establish effective evaluation methods to ensure the safety of iPS cells. At the same time, we have also focused our attention on the molecular mechanisms underlying the reprogramming process. At the end of the day, we would like to positively contribute to the achievement of successful regenerative medicine utilizing pluripotent stem cells based on the steady accumulation of knowledge in this important field of study.

Shinya Yamanaka M.D., Ph.D.Professor

Research and EducationWe previously were able to successfully transform fibroblasts into a pluripotent state using a set of four defined transcription factors (Oct3/4, Sox2, Klf4 and c-Myc) by means of retroviral transduction. These artificially established cells have both potentials and characteristics similar to those of embryonic stem (ES) cells, and thus are called induced Pluripotent Stem (iPS) cells. Because human iPS cells are expected to become useful tools for both better understanding various pathologies, as well as for the discovery of new drugs, this technology has thus been rapidly evolving. In addition, iPS cells are also a potentially useful source for cell transplantation without any danger of immunological rejection. We have conducted numerous analyses to improve the quality of iPS cells. According to previous results, we have identified several issues regarding iPS cells which still have to be overcome before they can be used for clinical application. We believe that it is important to understand the molecular mechanisms underlying the reprogramming process and the network of pluripotency for the achievement of our ultimate goal, namely the generation of clinical-grade iPS cells. Our field consists of seven groups, and each of them has a unique standpoint and background. By utilizing fusion, molecular and cellular biology techniques and bioinformatics, we have been continually evaluating the bottom line of reprogramming and pluripotency from various perspectives. At the end of the day, our results are expected to positively contribute to the identification of the best sources and methods for iPS cell generation, while also establishing stable culture conditions for effective clinical application.

Recent Publications1. Nakagawa, M., Takizawa, N., Narita, M., Ichisaka, T., and Yamanaka, S. Promotion of direct

reprogramming by transformation-deficient Myc. Proc Natl Acad Sci U S A. 107(32):14152-14157, 2010.

2. Yoshida, Y., Takahashi, K, Okita, K., Ichisaka, T., and Yamanaka, S. Hypoxia Enhances the Generation of Induced Pluripotent Stem Cells. Cell Stem Cell 5:237-241, 2009.

3. Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., Okita, K., and Yamanaka, S. Suppression of induced pluripotent stem cell generation by the p53–p21 pathway. Nature 460: 1132-1135, 2009.

4. Miura, K., Okada, Y., Aoi, T., Okada, A., Takahashi, K., Okita, K., Nakagawa, M., Koyanagi, M., Tanabe, K., Ohnuki, M., Ogawa, D., Ikeda, E., Okano, H., and Yamanaka, S. Variation in the safety of induced pluripotent stem cell lines. Nature Biotechnology 27: 743-745, 2009.

5. Okita, K., Nakagawa, M., Hong, H., Ichisaka, T., and Yamanaka, S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 322: 949-953, 2008.

❶ Human iPS cells generated with L-Myc (upper photo). Germline transmission of mouse L-Myc iPS cells (lower photo).

❷ Human iPS cells derived from adult human dermal fibroblasts. ❸ Cartilage derived from iPS cells putatively homozygous for the HLA-A, B, and DRB1 loci. ❹ Laboratory members

Reprogramming Science, Center for iPS Cell Research and Application (CiRA)Reprogramming Regulation FieldProfessor : Shinya Yamanaka TEL : 075-366-7044 FAX : 075-366-7042 e-mail : [email protected] URL : http://www.cira.kyoto-u.ac.jp:80/

yamanaka_group/?lang=en

Reprogramming Regulation Field

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The objective of this department is to disclose the molecular mechanisms of differentiation from induced pluripotent stem (iPS) cells into various types of tissue cells and to establish efficient and safe induction methods, which will contribute to the clinical application of iPS cells.

Junya Toguchida, M.D., Ph.D.Professor

Research and EducationiPS cells can be applied for various clinical fields including the investigation of pathogeneses of diseases, the discovery of drugs, and the cell therapy. For these applications, it is essential to establish the methods by which iPS cells can be efficiently and safely differentiated into target tissue-specific cells. Based on the information of the developmental biology, various culture conditions are employed to establish the most suitable method of differentiation induction. Current target cells include mesenchymal cells such as bone, cartilage, and muscles cells, cardiovascular cells, neural cells, and renal, pancreatic, and hepatic cells. Principal investigators for each part are responsible for the education of students, and the mutual exchange of information within the department is designed to expand the research field of each student.

Recent Publications1. Shibata K, Toguchida J, et al. Expression of the p16INK4A gene is associated closely with

senescence of human mesenchymal stem cells, and potentially silenced by DNA methylation during in vitro expansion. Stem Cells 25:2371-82 (2007)

2. Wataya T, Takahashi J, et al. Minimization of exogenous signals in ES cell culture induces rostral hypothalamic differentiation. Proc Natl Acad Sci USA 105: 11796-801 (2008)

3. Narazaki G, Yamashita JK et al. Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation 118: 498-506 (2008)

4. Chen S, Osafune K, et al. A small molecule that directs differentiation of human ESCs into the pancreatic lineage. Nat Chem Biol 5: 258-65 (2009)

❶ Cartilage-like tissue induced from human iPS cells

❷ D o p a m i n e r g i c neu rons i nduced from human iPS cells

❸ C a r d i o m y o c y t e s induced from human iPS cells

❹ Vascular structures induced from mouse iPS cells

❺ Hepatocytes induced from human iPS cells

❻ Pancreatic precursor cells induced from human iPS cells

Department of Cell growth and DifferentiationDifferentiation Induction FieldGroup Leader Professor : Junya Toguchida Associate Professor : Jun Takahashi, Jun Yamashita, Kenji Osafune TEL : +81-75-751-4134 FAX : +81-75-751-4646 e-mail : [email protected] URL : http://www.cira.kyoto-u.ac.jp/j/index.

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Differentiation Induction Field

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- Cell Growth and Differentiation - Center for iPS Cell Research and Application (CiRA)


At our laboratory, we are studying the pathophysiology and pathogenesis of various intractable disease by using patient-derived iPS cells, aiming at with a goal of applying iPS cells to clinical studies. For, efficient research on disease-specific iPS cells, it is necessary to establish and combine the following three experimental systems appropriately: (1) establishment of disease-specific iPS cells, (2) development of an optimal differentiation system capable of reflecting the features of disease, and (3) analysis of differentiation-induced cells. We are interested in and studying the congenital diseases including hematological diorders with bone marrow failure, primary immunodeficiency diseases, refractory pediatric neurological diseases, and congenital hearing loss1.*1 In collaboration with Prof. Juichi Ito of department of Otolaryngology, Graduate School of Medicine Kyoto University Tatsutoshi Nakahata M.D., Ph.D.

Professor

Research and EducationWe have already established more than 20 patient-derived iPS cells with 8 kinds of hematological, immunologica l , or neurologica l d iseases2 (including clones now being established). Some of these diseases have the biological features which make generation of iPS cells very difficult. We are enthusiastically trying to generate iPS cells associated with these diseases, because establishment of iPS cells from these patients will contribute to elucidating the mechanism of cellular reprogramming.We are working for improving hematopoietic cell differentiation systems and have established an original differentiation system which can recapitulate in vivo differentiation pathway. We use this system for disease modeling and analysis because it can generate various kinds of functional blood cells such as red blood cells, neutrophils, and platelets. Moreover, we are establishing in vivo reconstitution system for iPS cell-derived hematopoietic cells by transplanting them into immune-deficient NOG mice. In vitro differentiation systems for iPS cells into functional neurons or inner ear cells are also under development. Our goal is to elucidate pathophysiology of various diseases by using iPS cell-derived functional cells or tissues via appropriate differentiation systems. Since patient-derived iPS cells are considered as an useful tool for developing therapeutic drugs for intractable diseases, we will conduct screening of drugs and compounds which can alleviate in vitro phenotype, in order to contribute to management of patients suffering from intractable diseases. *2 including clones established in collaboration with Dr. Isao Asaka or Dr. Haruhisa Inoue, Center for iPS cell research and application, Kyoto University Recent Publications

1. Sakai H, Ito S, Nishikomori R, Takaoka Y, Kawai T, Saito M, Okafuji I, Yasumi T, Heike T, Nakahata T. : A case of early-onset sarcoidosis with a six-base deletion in the NOD2 gene. Rheumatology (Oxford). 49: 194-196, 2010.

2. Mizuno Y., Chang H., Umeda K., Niwa A., IwasaT., Awaya T., Fukada S., Hiroshi Yamamoto H., Yamanaka S., Nakahata T., Heike T.: Generation of skeletal muscle stem/progenitor cells from murine induced pluripotent stem cells. FASEB J. 24:2245-2253, 2010.

3. Kuroda Y., Kitada M., Wakao S., Nishikawa K., Tanimura Y., Makinoshima H., Goda M., Akashi H., Inutsuka A., Niwa A., Nabeshima Y., Nakahata T., Nabeshima Y., Fujiyoshi Y., Dezawa M.: Unique multipotent cells in adult human mesenchymal cell populations. Proc. Natl. Adad. Sci. USA 107:8639-8643, 2010.

4. Kumada T., Yamanaka Y., Kitano A., Shibata M.,Awaya T., Kato T., Okawa K.,Abe T., Oshima N., Nakahata T., Heike T.: Ttyh1, a Ca2+-binding protein localized to the endoplasmic reticulum, is required for early emblyonic development. Develop. Dynam. 239:2233-2245,2010.

5. Kaichi S., Hasegawa K., Takaya T., Yokoo N., Mima T., Kawamura T., Morimoto T., Baba S., Doi H., Yamanaka S., Nakahata T., Heike T.: Cell line-dependent differentiation of induced pluripotent stem cells into cardiomyocytes in mice. Cardiovascular Res. 88: 314-323, 2010

❶ Hematopoietic mesodermal colony

❷ Hematopoietic colonies

❸ Blood cells ❹ Very immature

hematopoietic colonies

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Professor : Tatsutoshi NAKAHATA TEL : +81-75-366-7033 FAX : +81-75-366-7091 e-mail : [email protected]

Assistant Professor : Megumu Saito TEL : +81-75-366-7085 FAX : +81-75-366-7088 e-mail : [email protected] URL : http://www.cira.kyoto-u.ac.jp/nakahata/

Disease modeling with patient-derived iPS cells

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Caring for the ill persons is the origin of medicine. Prevention of disease is another matter of importance. Prevention includes preventing the occurrence of a disease (primary prevention) and arresting the progression of a disease through early diagnosis and early treatment (secondary prevention). Kyoto University Health Service is the primary-care facility for preventive services, such as health checkups and promotion, for students and employees of Kyoto University. We also provide health guidance and counseling as well as primary care for diseases and injuries. In our practice, we conduct epidemiological research for disease control and prevention, and develop various healthcare systems. In this way, we disseminate evidence from the on-site daily clinical routine.

Takashi Kawamura, M.D., Ph.D.Professor

Research and Education“Sudden death of employees frequently occurs in April and on weekends.” “Water-gargling prevents common cold.” ”Chest compression-only resuscitation is the best way for lay bystanders.” “Introduction of hemodialysis in IgA nephropathy can be predicted by blood pressure, urine protein, urine blood, serum albumin, etc.” ”Adverse events of gefitinib are more common among patients with some characteristics.” We are studying quite common health problems to contribute to daily healthcare. Our study tool is epidemiology. We collaborate with many medical and governmental facilities all over the country.In the School of Public Health, we participate in a core-course on “Epidemiology” which helps us to evaluate the causes of a disease and the effectiveness of medical procedures through observation and intervention, and also in courses on ”Study protocol writing and study management” and ”Cardinal points in clinical research practice” for students who intend to carry out clinical researches. We continuously mentor each student assigned to our department. As a graduate school student, some medical qualifications are required because we study in practices. See the webpage of the University Health Service.

Recent Publications1. Kawamura T, Kondo H, Hirai M, et al. Sudden death in the working population: a collaborative

study in central Japan. Eur Heart J 1999; 20: 338-343. 2. Satomura K, Kitamura T, Kawamura T, et al. Prevention of upper respiratory tract infections by

gargling: a randomized trial. Am J Prev Med 2005; 29: 302-307. 3. Iwami T, Kawamura T, Hiraide A, et al. Effectiveness of bystander-initiated cardiac-only

resuscitation for patients with out-of-hospital cardiac arrest. Circulation 2007; 116: 2900-2907. 4. Goto M, Kawamura T, Ando M, et al. A scoring system to predict renal outcome in IgA

nephropathy: a nationwide 10-year prospective cohort study. Nephrol Dial Transplant 2009; 24: 3068-3074.

5. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small cell lung cancer patients treated with gefitinib. J Clin Oncol 2006; 24: 2549-2556.

❶ Randomized controlled t r ia l evaluat ing the preventive effect of gargling for common cold (Ref No.2)

❷ Patients cohort study ident i fy ing the r isk fac to rs o f adverse events by gefitinib (Ref No.5)

Preventive Services(Kyoto University Health Service)Professor : Takashi Kawamura Associate Professor : Kazumi Takemoto, Masahiko Ando Senior Lecturer : Masashi Goto Assistant Professor : Taku Iwami, Teruhisa Uwatoko TEL : +81-75-753-2400 FAX : +81-75-753-2424 e-mail : [email protected] URL : http://www.kyoto-u.ac.jp/health/kuhc-

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Preventive Services

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- Kyoto University Health Service


How can our body be created from a single cell, the egg? What defines totipotency in the egg? Seeking for answers to these questions, our current projects focus on understanding the mechanism by which the initial asymmetry is established in the mammalian embryo. Direct observation of dynamic morphogenesis is a central feature of our research, and we adopt multi-disciplinary strategies for a systems-level understanding of mammalian development. Your will study in an international environment, collaborating with laboratories in the Max-Planck Institute (http://www.mpi-muenster.mpg.de/en/index.html) and European Molecular Biology Laboratory (EMBL : http://www.embl.de/).

Takashi Hiiragi, M.D., Ph.D.Professor

Research and EducationThe ultimate goal of the research in our laboratory is the understanding of totipotency: what defines totipotency and what makes cell totipotent. Germ-line cells, oocyte and sperm, are highly differentiated but nevertheless able to regain totipotency by forming a zygote, thereby initiating embryonic development in the next generation. A prerequisite for understanding totipotency is the knowledge of developmental mechanisms during transition from oocyte to embryo and early embryogenesis. Our current research thus focuses on a systems-level understanding of the principles underlying early mammalian development.We adopt a wide variety of experimental approaches in order to understand the program at a molecular, cellular and systems level; in particular, 4D live-imaging, fluorescence-based gene-trap screen, gene expression profile of individual blastomeres, experimental micromanipulation and computer simulation of the blastocyst morphogenesis. Questions to be addressed in your PhD study include:- When and how is the initial lineage established in the mouse embryo?- H o w c a n t h e m o u s e e m b r y o c o u n t i t s developmental timing?See http://www.embl.de/ for detail.

Recent Publications1. Honda, H., Motosugi, N., Nagai, T., Tanemura, M. and Hiiragi, T. (2008). Computer simulation of

emerging asymmetry in the mammalian blastocyst. Development 135:1407-1414. 2. Dietrich, J.-E. and Hiiragi, T. (2007). Stochastic patterning in the early mouse embryo.

Development 134:4219-4231. 3. Motosugi, N., Dietrich, J-E., Polanski, Z., Solter, D. and Hiiragi, T. (2006). Space asymmetry

directs preferential sperm entry in the absence of polarity in the mouse oocyte. PLoS Biology 4:e135.

4. Motosugi, N., Bauer, T., Polanski, Z., Solter, D. and Hiiragi, T. (2005). Polarity of the mouse embryo is established at blastocyst and is not prepatterned. Genes & Development 19:1081-1092.

5. Hiiragi, T. and Solter, D. (2004). First cleavage plane of the mouse egg is not predetermined but defined by the topology of the two apposing pronuclei. Nature 430:360-364

❶ Totipotent egg ❷ Blastocyst morphogenesis ❸ Computer simulation of blastocyst morphogenesis ❹ ICM-specific reporter expression in a gene-trap

mouse

Developmental BiologyProfessor : Takashi Hiiragi TEL : +81-75-753-9844 FAX : +81-75-753-9820 e-mail : [email protected] URL : http://www.icems.kyoto-u.ac.jp/e/ppl/

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Developmental Biology

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- Institute for Integrated Cell-Material Sciences (iCeMS)


Brain development itself is a great mystery, which has been enhanced scientists for many decades. Recent progress in molecular embryology has isolated a huge number of regulatory genes involved in this process. This department focuses on molecular and cellular mechanism of the regional specificity in developing brain tissues. This exciting field of research is also contributing to the progress of regenerative medicine, especially ES cell-based therapeutics of neurological diseases.

Yoshiki Sasai, M.D., Ph.D.Kyoto University Visiting Professor

Research and EducationBy using the affiliation graduate school system, Kyo to Un ive r s i t y and RIKEN Cen te r fo r Developmental Biology cooperate in education and training of graduate students. We also hold a summer intensive course for developmental and regeneration study together at RIKEN. ■Focus 1"Induction and Early Patterning of Vertebrate Neural Tissues"We wish to understand the molecular and cellular bases of vertebrate neural induction (i.e., the initial step of neurogenesis) and early ectodermal patterning following the primary induction. For this reaserch, the primary experimental animal we use is Xenopus.

"Secreted Patterning Signals that Provide Positional Information in CNS Development"We wish to identify new patterning signals that give positional information to differentiating neural cells in the central nervous system (CNS), and analyzed their in vivo roles. We use Xenopus, chick and mice for this study.

"Establishment of in vitro Neural Differentiation Systems Using ES Cells"By using mouse ES cells, we attempt to establish efficient in vitro systems of neural differentiation that mimics mammalian neurogenesis. By using these systems, we wish to understand signals that define the positional identity of cells in the embryonic nervous systems.

"Application of in vitro Produced Neural and Sensory Cells to Regenerative Medicine"The goal of this study is to establish the technical bases of the production of neurons to be used in regenerative medicine for diseases, such as Parkinson’s disease and retinal degeneration. This topic is studied in close collaboration with Kyoto University Hospital.

Recent Publications1. Eiraku, M, Watanabe, K., Matsuo-Takasaki, M., Kawada, M., Yonemura, S., Matsumura, M.,

Wataya, T., Nishiyama, A., Muguruma, K. and Sasai, Y. (2008) Self-Organized Formation of Polarized Cortical Tissues from ES cells and its Active Manipulation by Extrinsic Signals. Cell Stem Cell 3, 519-532

2. Inomata, H., Haraguchi, T. and Sasai, Y. (2008) Robust Stability of the Embryonic Dorsal Axial Pattern Requires ONT1, a Secreted Scaffold for Chordin Degradation. Cell 134, 854-865.

3. Sasai, N., Yakura, R,, Kamiya, D., Nakazawa, Y. and Sasai, Y. (2008) Ectodermal Factor Restricts Mesoderm Differentiation by Inhibiting p53. Cell 133, 878–890

4. Muguruma, K., Nishiyama, A., Ono, Y., Miyawaki, H., Mizuhara, E., Hori, S., Kakizuka, A., Obata, K., Yanagawa, Y., Hirano, T. and Sasai, Y. (2010) Ontogeny-recapitulating generation and tissue integration of ES cell-derived cerebellar Purkinje cells. Nature Neurosci 13, 1171 - 1180

5. Kamiya, D., Banno, S., Sasai, N., Watanabe, K., Kawada, M., Yakura, R., Jakt , L.M., Nishikawa, S. and Sasai. Y. (2011) Intrinsic transition of ES cell differentiation into neural progenitors. Nature 470, 503-509

❶ Dopaminergic neurons (yellow) and other neurons (red) induced from primate ES cells by the SDIA method.

❷ Expression of the CNS marker Sox2 (blue) and the neural crest marker FoxD3 (indigo) in the Xenopus neurula. We have proved that Sox2 and FoxD3 are essential for development of the CNS and the neural crest, respectively.

❸ Discussion on data

Medical Embryology Laboratory for Organogenesis and Neurogenesis RIKEN Center for Developmental BiologyGroup Director : Yoshiki Sasai TEL : +81-78-306-1841 FAX : +81-78-306-1854 e-mail : [email protected] URL : http://www.cdb.riken.jp/sasai/

Medical Embryology Laboratory for Organogenesis and Neurogenesis

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- Affiliate Graduate School - RIKEN Center for Developmental Biology


We use the mouse as a model system to study cloning under a range of experimental conditions with the goals of achieving improvements in the efficiency of the cloning procedure, gaining a better understanding of reprogramming mechanisms and analyzing the properties of ES cells derived via somatic nuclear transfer. We also use nuclear transfer technology to develop methods for preserving embryonic lethal and infertile strains of laboratory mice, and continue to explore the development of new and better techniques for sperm and oocyte preservation and other reproductive biological research technologies.

Teruhiko Wakayama, Ph. D.Kyoto University Visiting Associate Professor

Research and EducationOur general research interest is to elucidate how a completely differentiated cell can be reprogrammed by oocyte cytoplasm and develop to full term. Gamete cells themselves are of course also differentiated and highly specialized cells that function in the generation of offspring, and these cells (spermatozoa and oocytes) do not exhibit totipotency until fertilization. After fertilization, the nuclei of both the sperm and the oocyte are reprogrammed and gain totipotency within the cytoplasm of the oocyte. We have hypothesized that, in cloning experiments, somatic cell nuclei undergo reprogramming in an unfertilized oocyte in a manner similar to that of gametes in fertilization; the oocytes ability to reprogram somatic cell nuclei seems otherwise inexplicable. For this reason, although our main research interest is somatic cell nuclear transfer, we are also working to clarify the mechanisms of gametogenesis and fertilization, a better understanding of which would seem likely help us to gain insight into the mechanisms of nuclear reprogramming and animal cloning. We are also interested in the development of new techniques for the production of offspring from immature gametes or infertile mice lacking germ cells, as well as for the preservation of gamete cells without freezing, as the development of such techniques may help us to extend our ability to conduct experiments. Our ongoing projects are detailed below, organized into four foci.

Recent Publications1. Wakayama et al. (2005) Propagation of an Infertile Hermaphrodite Mouse Lacking Germ Cells,

Using Nuclear Transfer and Embryonic Stem Cell Technology. Proc. Natl. Acad. Sci. USA 102:29-33. (Cover article of issue)

2. Wakayama et al., (2007) Establishment of mouse embryonic stem cell lines from somatic cell nuclei by nuclear transfer into aged, fertilization-failure mouse oocytes. Curr Biol. 17: R120-R121

3. Tabar et al., (2008) Therapeutic cloning in individual parkinsonian mice. Nat. Med. 14: 379-381 4. Wakayama et al., (2008) Production of healthy cloned mice from bodies frozen at -20°C for 16

years. Proc Natl Acad Sci U S A. 105:17318–17322

❶ Nuc lea r t rans fe r ; Mouse oocyte was fixed by holding pipette and donor somatic nucleus was injected into oocyte by micromanipulator.

❷ Mouse frozen at -20oC for 16 years

❸ Healthy cloned mouse derived from the frozen mouse

❹ Abnormality of cloned mice. Left is cloned mouse and its placentomegaly.

❺ Lab personnels

Reproductive BiotechnologyLaboratory for Genomic Reprogramming RIKEN Center for Developmental BiologyTeam Leader : Teruhiko Wakayama TEL : +81-78-306-3049 FAX : +81-78-306-3095 e-mail : [email protected] URL : http://www.cdb.riken.go.jp/grp/

Reproductive Biotechnology Laboratory for Genomic Reprogramming

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More than a hundred thousand of neurons reside in the human brain. These enormous numbers of neurons are variable in terms of their morphologies, gene expressions, neurotransmitter types and functions. How is the information to control both precise identities of these neurons and formation of complicated neural networks programmed on our DNA? How does each neuron and glia choose their cell fate from common progenitors? How does each neuron precisely recognize other neurons and form correct synapses? How does each neural circuit realize physiological function and behavior? Finally, how is malformation or dysfunction of these steps related to our diseases? We are challenging these problems by using the retina as a model system to explore the CNS. Our main technical approaches are molecular biology, histology, physiology, and mouse molecular genetics using KO/transgenic mice including BAC transgenic and conditional KO mice. Takahisa Furukawa, M.D. Ph.D.

Kyoto University Visiting Professor

Research and Education1.Molecular mechanisms of synapse formation in the retina and brain2.Molecular mechanisms of primary cilia formation and function in the CNS3.Mechanisms of cell fate determination of the vertebrate retina4.Functional analysis of microRNA expressed in the retina and brain5.Generation of KO/transgenic mice and analysis of their visual function

It is important for research training to work under a good mentor, absorb both basic and leading-edge knowledge in the field, learn how to design experiments, acquire experimental skills, analyze data, and learn how to write a paper.

1. Training of in vivo experimentsWe perform various in vivo experiments to clarify gene function. Unless you understand importance of a molecule in vivo, you may be not sure why you study that molecule.2. Learning various experimental skillsIn our lab, we use broad range of experimental techniques including molecular biology, histology, cell culture and animal experiments (transgenic mouse, KO mouse, zebrafish). Therefore, graduate students can do a good training through learning these techniques and experiments.3. Acquirement of broad range of knowledgeWe do reading circle of textbooks and research papers. We want to encourage young scientists to learn about various fields. That is important for your future when you start your own research.4. Graduate school student/postdoc from abroadWe welcome graduate school students and postdocs from outside Japan to our lab. I am an adjunct professor of Kyoto University Graduate School of Medicine. An applicant can apply for either or both of these graduate schools. An applicant needs to find a fellowship. We are happy to support applicants to apply for a JSPS/MEXT fellowship or other available fellowships.

Recent Publications1. Omori, Y., Chaya, T., Katoh, K., Kajimura, N., Sato, S., Muraoka, K., Ueno, S., Koyasu, T., Kondo,

M. & Furukawa, T. Negative regulation of ciliary length by ciliary male germ cell-associated kinase(Mak) is required

for retinal photoreceptor survival. Proc. Natl. Acad. Sci. U.S.A. 107(52), 22671-22676 (2010) 2. Katoh, K., Omori, Y., Onishi, A., Sato, S., Kondo, M. & Furukawa, T. Blimp1 suppresses Chx10 expression in differentiating retinal photoreceptor precursors to ensure

proper photoreceptor development. J. of Neurosci. 30(19), 6515-6526 (2010) 3. Koike, C., Obara, T., Uriu, Y., Numata, T., Sanuki, R., Miyata, K.,Koyasu, T., Ueno, S., Funabiki,

K., Tani, A., Ueda, H., Kondo, M., Mori Y.,Tachibana, M. & Furukawa, T. TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade.

Proc. Natl. Acad. Sci. USA, 107, 332-337 (2009) 4. Sato, S., Omori, Y., Katoh, K., Kondo, M., Kanagawa, M., Miyata, K., Funabiki, K., Koyasu, T., Kajimura, N., Miyoshi, T., Sawai, H., Kobayashi,K., Tani, A., Toda, T.,

Usukura, J., Tano, Y., Fujikado, T. & Furukawa, T. Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation. Nat.

Neurosci., 11, 923-931 (2008) 5. Nishida, A., Furukawa, A., Koike, C., Tano, Y., Aizawa, S., Matsuo, I. &Furukawa, T. Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development. Nat.

Neurosci. 6, 1255-1263 (2003)

❶ Analysis of rod ribbon synapse in the pikachurin KO retina by electron tomography. In the pikachurin KO retina, bipolar dendritic terminus did not invaginate into the

photoreceptor ribbon synapse. ❷ Lab members Developmental Biology

Osaka Bioscience InstituteHead : Takahisa Furukawa Vice-Head : Yoshihiro Omori Research Associate : Koji Terada, Akishi Onishi Postdoctoral Associate : Yuki Muranishi Research Collaborator : Rikako Sanuki, Kimiko Katoh Graduate Student : Fumiyuki Araki, Koji Mizuhashi, Shoichi Irie, Taro Chaya, Satoshi Watanabe Technical Assistant : Akiko Tani, Mikiko Kadowaki, Toshinori Tsujii, Aiko Ishimaru, Yukiko Saioka TEL : +81-6-6872-4853 FAX : +81-6-6872-3933 e-mail : [email protected] URL : http://www.obi.or.jp/dept4/english.html

Developmental Biology

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- Affiliate Graduate School - Osaka Bioscience Institute


The retina has been called the "approachable part of the brain," owing to its relatively simple structure and its location near the body surface, and for these reasons it serves as a useful and experimentally amenable model of the central nervous system. Until very recently, it was thought that, in adult mammals, the retina was entirely incapable of regenerating, but we now know that at least new retinal neurons can be generated after being damaged. This has opened up new hope that the ability to regenerate neurons and even to reconstitute the neural network may be retained in the adult retina. We are now exploring the exciting prospect that, by transplanting cells from outside of the retina or by regeneration from intrinsic progenitor cells, it may one day be possible to restore lost function to damaged retinas.

Masayo Takahashi,M.D.,Ph.D.Kyoto University Visiting Associate Professor

Research and EducationOur research into retinal regeneration seeks to achieve clinical applications by developing methods for inducing stem cells to differentiate into retinal neurons and pigmented epithelial cells in sufficient quantities for use in the treatment of patients suffering from conditions in which such cells have been damaged or lost, and to ensure that such cells establish viable grafts on transplantation and induce the reconstitution of functional neural networks. We also hope to develop means of promoting true regeneration by activating endogenous stem cells to replace cells lost to trauma or disease and thus repair damaged tissues. Access to a broad spectrum of developmental biological research information will be key to the achievement of these goals, and we appreciate the opportunities for exchange that working in the environment provided by the RIKEN CDB provides. Therapeutic applications cannot be developed from basic research alone; the clinical approach - a thorough understanding of the medical condition to be treated - is equally important. For conditions such as retinitis pigmentosa, even the successful transplantation of cells in animal models may not necessarily be translatable to a human clinical therapy without an understanding of the underlying genetics and possible immunological involvement. Our goal is to study retinal regeneration based on both a strong foundation in basic research and solid clinical evidence.

Recent Publications1. Takahashi M, et al. Widespread integration and survival of adult-derived neural progenitor cells in

the developing optic retina. Mol. Cell. Neurosci. 12:340-348. 1998 2. Haruta et al. Induction of photoreceptor-specific phenotypes in adult mammalian iris tissue. Nat

Neurosci. 4:1163-1164 2001 3. Ooto et al. Potential for neural regeneration after neurotoxic injury in the adult mammalian retina.

Proc Natl Acad Sci USA. 101:13654-13659. 2004 4. Osakada F et al. Toward the generation of rod and cone photoreceptors from mouse, monkey and

human embryonic stem cells. Nat Biotech. 26:215-224. 2007 5. Zin JB et al. Identifying pathogenic genetic background of simplex or multiplex retinitis

pigmentosa patients: a large scale mutation screening study. J Med Genet. 45:465-472. 2008

❶ Newly generated photoreceptor cells in the damaged adult rat retina

❷ photoreceptor cells differentiated from human ES cells

❸ human iPS cells ❹ Laboratory members

Application biology and regenerative medicineLaboratory for Retinal RegenerationRIKEN Center for Developmental BiologyTeam Leader : Masayo Takahashi Research Scientist : Michiko Mandai, Kohei Homma, Akiko Suga, Zi-Bing Jin TEL : +81-78-306-3305 FAX : +81-78-306-3303 e-mail : [email protected] URL : http://www.retinastem.jp/xoops/

Application biology and regenerative medicine laboratory for Retinal Regeneration

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Graduate students interested in the methods of biostatistics and the conduct of epidemiologic research and clinical trials are welcomed. This Department offers programs of study leading to a master's degree and a doctoral degree. The Master of Public Health (MPH) degree program is designed to provide basic training in biostatistics as applied to a broad spectrum of health-related problems. The doctoral degree program is designed to provide advanced, research oriented training in methods of biostatistics.

T. Shun Sato, Ph.D.Professor

Research and EducationMajor research fields are biostatistics methodology and conducts of epidemiologic studies and clinical trails. In methodological work, new epidemiologic study designs which are efficient and convenient are investigated for providing new sampling and analysis methods. Causal inference is the most challenging methodological research field. Estimation of causal parameters in experimental and observational studies is developing. Several collaborative studies in epidemiology and clinical trials are ongoing.Department of Biostatistics offers “Fundamentals of Biostatistics”, “Introduction to Statistical Computing and Data Management”, “Intermediate Biostatistics”, and “Health Data Processing Lab”. We give introduction to concepts of randomization, causal effects, and confounding, designs of clinical trials and observational studies. Topics include randomization, experimentation, measurement, probability, confidence intervals, and tests of hypotheses.

Recent Publications1. Sozu T, Sugimoto T, Hamasaki T. Sample size determination in clinical trials with multiple co-

primary endpoints. Statistics in Medicine 2010; 29: 2169-2179. 2. Noma H, Matsui S, Omori T, Sato T. Bayesian ranking and selection methods using hierarchical

mixture models in microarray studies. Biostatistics 2010; 11: 281-289. 3. Okusaka T, Kasugai H, Shioyama Y, Tanaka K, Kudo M, Saisho H, Osaki Y, Sata M, Fujiyama

S, Kumada T, Sato K, Yamamota S, Hinotsu S, Sato T. Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a ramdomized phase III trail. Journal of Hepatology 2009; 51: 1030-1036.

4. Inoue T, Fujita T, Kishimoto H, Makino T, Nakamura T, Nakamura T, Sato T, Yamasaki K. Randomized controlled study on the prevention of osteoporostic fractures (OF Study): A phase IV clinical study of 15-mg menatetrenone capsules. Journal of Bone and Mineral Metabolism 2009; 27: 66-75.

5. Yonemoto N, Furuse J, Okusaka T, Yamao K, Funakoshi A, Ohkawa S, Boku N, Tanaka K, Nagase M, Saisho H, Sato T. A multi-center retrospective analysis of survival benefits of chemotherapy for unresectable biliary tract cancer. Japanese Journal of Clinical Oncology 2007; 37: 843-851.

❶ Biostatistics Class

BiostatisticsProfessor : Tosiya Sato Associate Professor : Takashi Sozu TEL : +81-75-753-4475 FAX : +81-75-753-4487 e-mail : [email protected] URL : http://www.kbs.med.kyoto-u.ac.jp/

Biostatistics

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- Public Health - Health Analyses


Clinical medicine is a highly social practice. Because it applies findings from biomedical scientific research to people living in a complex social environment, the medical community is obliged to assess the appropriateness, effectiveness, and efficiency of healthcare. With this in mind, we incorporate clinical medicine, epidemiology, statistics, psychometrics, and other fields into research aimed at measuring and improving the healthcare quality and patients' outcomes. We welcome those who share our outlook, our values, and our commitment to studying and improving clinical practice.

Shunichi Fukuhara, M.D., F.A.C.P.Professor

Research and EducationWhat are the goals of health care? How should it be judged? For example, the goal may be “to make patients better", but in what sense? Surely the mere prolongation of life is not enough. Perhaps the results of medical-laboratory tests can be used to distinguish success from failure, but how should we interpret test results that are inconsistent with symptoms? In evaluations of the effectiveness of medical interventions, what indicators are relevant to patients and to society?“Quality of health care"" has become a popular topic, but how is it defined in practice? Consider just a few of the questions that can arise with regard to surgery: Is comparison of death rates after surgery valid? Do rates of post-surgical death stabilize once a certain level of experience is reached? When evaluating studies of post-surgical death rates, can we trust the statistical adjustments for the severity of illness?Our department focuses its efforts on such questions. This field has been called “health services research". While seeking to understand health care services in their scientific, socio-cultural, and economic environment, we often focus on the outcomes of those services from the viewpoints of patients and of society. Recent examples of our activities include participation in an international study of dialysis outcomes and practice patterns, and sending our staff to the University of California (Los Angeles) to participate in research on the quality of care of the elderly. In cooperation with national and international institutions, we carry out and promote research in these and other areas with a broad perspective and with the highest possible standards of scientific rigor.

Recent Publications1. Higashi T, Wenger NS, Adams JL, et al. Patients with More Medical Conditions Receive Better

Quality Care: Analysis of data from three large surveys. New England Journal of Medicine, 356:2496-504, 2007

2. Fukuhara S, Yamazaki S, Hayashino Y, et al. Patient-reported quality of life in end-stage renal disease. Nature Clinical Practice, 3:352-3, 2007

3. Yamazaki S, Nitta H, Ono M, et al. Intracerebral hemorrhage associated with hourly concentration of ambient particulate matter: case-crossover analysis. Occupational Environmental Medicine, 64:17-27, 2007

4. Takegami M, Hayashino Y, Chin K, et al. Simple four-variable screening tool for identification of patients with sleep-disordered breathing. Sleep, 32(7):939-48, 2009

5. Suzukamo Y, Fukuhara S, Green J, et al. Validation, testing of a three-component model of SF-36 scores. Journal of Clinical Epidemiology (in press 2011)

6. Hayashino Y, Fukuhara S. Diabetes in Asia. Lancet 2010;375:981-2

❶ ref.4 ❷ ref.5 ❸ ref.3

Epidemiology and Healthcare ResearchProfessor : Shunichi Fukuhara Associate Professor : Shin Yamazaki, Yasuaki Hayashino Senior Lecturer : Yosuke Yamamoto, Naoki Kakudate Assistant Professor : Misa Takegami FAX : +81-75-753-4644 URL : http://www.epikyoto-u.jp


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Pharmacoepidemiology is a natural crossing of two specialties: clinical pharmacology and clinical epidemiology. It aims to describe, explain, predict, and control the uses and effects (beneficial and adverse events) of drugs and biologics in human populations through the chemistry, manufacturing, and control (CMC) evaluations, non-clinical analyses, and clinical trial design. We also perform active research and development of novel immunotoxins, cytotoxins and cancer vaccines for the treatment of cancer.

Koji Kawakami, M.D., Ph.D.Professor

Research and EducationWe perform education and research on the planning, preparation, and evaluation of clinical trials. Researches on new drug approval and regulatory systems in Japan, US and other countries are also discussed. Translational research which is the bridging of basic science to clinical application, and the development of new therapeutics utilizing biotechnology needs to undergo clinical trials to evaluate their safety, tolerability, and efficacy. Drug development requires chemistry, manufacturing, and controls (CMC), non-clinical analyses, and clinical protocol designs. Regulatory affairs of pharmaceutical companies or academic institutes work with the regulatory authority to initiate any clinical trials. Along with the ongoing and completion of clinical trials several issues including data analysis, evaluation of adverse events, post-marketing evaluation processes, and comparative effectiveness research (CER) are involved. Thus, we educate individuals and perform research on the entire process of drug development and clinical usage. In addition, we initiate active research projects on immunotoxins approach utilizing novel hybrid peptide for the treatment of cancer and inflammation. During the development of such biologics, on-the-job-training involving the drug safety assessment and evaluation of drug efficacy is being performed.

Recent Publications1. Ueyama H et al. Chromosomal variability of human mesenchymal stem cells cultured under

hypoxic condition. J. Cell Mol Med., in press, 2011. 2. Horibe T, Kohno M, Haramoto M, Ohara K, Kawakami K. Designed hybrid TPR peptide targeting

Hsp90 as a novel anticancer agent. J. Translational Med., in press, 2011. 3. Tada N et al. The current status of umbilical cord blood collection in Japanese medical centers:

survey from the obstetricians. Transfusion Apheresis Sci., in press, 2011. 4. Kohno M et al. A novel hybrid peptide targeting EGFR-expressing cancers. Eur. J. Cancer, in press,

2011. 5. Kobayashi Y, Hayashino Y, Takagaki N, Hinotsu S, Jackson JL, Kawakami K. Diagnostic

performance of chromoendoscopy and narrow band imaging for colonic neoplasms: meta-analysis. Colorectal Dis., in press, 2011.

❶ Investigational New Drug, +: New Drug Application ❷ Group picture ❸ Hybrid peptide therapeutics ❹ Immunotoxin book

PharmacoepidemiologyProfessor : Koji Kawakami, MD, PhD Associate Professor : Shiro Hinotsu, MD, PhD Program-Specific Assistant Professor : Tomohisa Horibe, PhD Hisashi Urushihara, DrPH TEL : +81-75-753-9469 FAX : +81-75-753-4469 e-mail : [email protected] URL : http://square.umin.ac.jp/kupe/

Pharmacoepidemiology

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Study of human diseases based on genetic information in the human genome is one of the most important subjects in the Post Genome Project. In particular, to overcome human multigenetic disorders, it is essential to perform trans-ethnic genetic analyses of human genome variations. In our laboratory, we perform SNP identification and genotyping of candidate genes of multigenetic diseases using DNA samples of patients and control subjects from different ethnic origins. We also work on the construction of a comprehensive SNP database of different multigenetic diseases which integrates genetic and clinical information using the latest bioinformatic and statistical genetic tools. We try to establish a new generation genome variation-based genomic strategy which will directly linked to clinical research and therapeutics.

Fumihiko Matsuda, Ph.D.Professor

Research and EducationWe have established an extensive international collaboration for ‘Genomic Epidemiology of Human Multigenetic Disorders’ with Centre National de Genotypage (CNG) in France. We focus on diseases related to the immune system such as Rheumatoid Arthritis, Lupus, Hyperthyroidism and AIDS, and those in which DNA repair mechanism is involved such as cancer. We have started a systematic SNP identification using a standard panel of DNA samples from multiple ethnic groups (Caucasians, Japanese, Africans, Thai). Based on the SNP catalog obtained, we undertake a large-scale case/control study by genotyping SNPs on an epidemiological scale (sample scale of > 1,000 individuals). Results are deposited in a disease-based genetic database which contains information of genes and their genetic variations combined with patient’s clinical information. Extensive statistical analyses is performed using a variety of statistical programs developed from joint research with CNG and The Rockefeller University in U.S.A. Comparison of genotypes between patients and controls among different ethnicities leads to the identification of disease-specific and ethnicity-specific genome variations. Annotated data will be made available to the scientific community as basic genetic information of diseases for future development of diagnostics and individual-based therapy (taylor-made medicine).

Recent Publications1. SEARCH Collaborative Group, Link, E., Parish, S., Armitage, J., Bowman, L., Heath, S., Matsuda,

F., Gut, I., Lathrop, M. and Collins, R. (2008) SLCO1B1 variants and statin-induced myopathy--a genomewide study. N. Engl. J. Med. 359, 789-799.

2. McKay, J.D. et al. (2008) Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404-1406 3. Wada, M., Marusawa, H., Yamada, R., Nasu, A., Osaki, Y., Kudo, M., Nabeshima, M., Fukuda, Y.,

Chiba, T. and Matsuda, F. (2009) Association of genetic polymorphisms with interferon-induced haematologic adverse effects in chronic hepatitis C patients. J. Viral. Hepat. 16, 388-396.

4. Nakanishi, H., Yamada, R., Gotoh, N., Hayashi, H., Yamashiro, K., Shimada, N., Ohno-Matsui, K., Mochizuki, M., Saito, M., Iida, T., Matsuo, K., Tajima, K., Yoshimura, N. and *Matsuda, F. (2009) A Genome-Wide Association Analysis Identified a Novel Susceptible Locus for Pathological Myopia at 11q24.1. PLoS Genetics Epub 2009 Sep 25.

5. Takahashi, M., Saenko, V. A., Rogounovitch T. I., Kawaguchi, T., Drozd, V. M., Takigawa-Imamura, H., Natallia M. Akulevich, N. M., Ratanajaraya, C., Mitsutake, N., Takamura, N., Danilova, L. I., Lushchik, M. L., Demidchik, Y. E., Heath, S., Yamada, R., Lathrop, M., Matsuda, F. and Yamashita, S. (2010) The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Hum. Mol. Genet. Mar 30. [Epub ahead of print]

6. Nalpas, B., Lavialle-Meziani, R., Plancoulaine, S., Jouanguy, E., Nalpas, A., Munteanu, M., Charlotte, F., Ranque, B., Patin, E., Heath, S., Fontaine, H., Vallet-Pichard, A., Pontoire, D., Bourlière, M., Casanova, J. L., Lathrop, M., Bréchot, C., Poynard, T., Matsuda, F., Pol, S. and Abel, L. (2010) Interferon-γ receptor 2 gene variants are associated with liver fibrosis in patients with chronic hepatitis C infection. Gut. In the press

❶ Laboratry members

Human Disease Genomics(Center for Genomic Medicine)Professor : Fumihiko Matsuda Associate Professor : Hiroshi Kadotani Associate Professor (Industry-Academia Collaboration) : Yoshiki Murakami Assistant Professor : Meiko Takahashi TEL : +81-75-753-4661 FAX : +81-75-753-9314 e-mail : [email protected]

Human Disease Genomics

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The mission of the Department of Healthcare Economics and Quality Management is to contribute to the improvement of the quality and efficiency of health systems by means of research, development, education and professional practice. To tackle and solve problems of quality and cost in health and health care, the Department applies multi- and inter-disciplinary fields of quantitative and qualitative sciences and technologies.

Yuichi Imanaka, M.D., M.P.H., Dr.Med.Sci., Ph.D.Professor

Research and EducationEducation and TrainingTo produce, in succession, and support highly-qualified researchers who leads the emerging area of health care quality, economics, policy and management and highly-qualified managers/directors who directly commit themselves in the new arena of the improvement of systems of health care; To develop a productive and mutually growing network with those inside and outside to improve health and health care system through the expertise of the network member; To systematize, improve and establish the education and training systems for academic and management works.

Research and DevelopmentTo produce academic research outputs contributory to health systems improvement through establishing more p roduc t ive work sys t ems and more effective collaborative networks; To develop "soft technologies" in succession on a stable basis which are to be actually and effectively implemented in the health policies and systems - examples are healthcare performance indicators, casemix classification and severity adjustment methodology, quality and safety management standards for accreditation, costing manuals for health care; To be a productive research team internationally renowned in the area of health care quality, economics, policy and management.

Degrees to be OfferedDoctor of Medical Science (DrMedSci or PhD): It usually takes 4 years. Doctor of Public Health Science (DrPH or PhD): It takes 3 years, usually after MPH. Master of Public Health (MPH): It usually takes 2 years, and also provides 1-year course. Additional information may be found on our Department home page.

Recent Publications1. Difference in lifetime medical expenditures between male smokers and non-smokers. Health

Policy. 2010 ;94(1):84-9. 2. Impact of system-level activities and reporting design on the number of incident reports for patient

safety. Quality & Safety in Health Care. 2010;19(2):122-7. 3. An outcome prediction model for adult intensive care. Critical Care and Resuscitation. 2010

;12:96-103. 4. Healthcare-associated infections in acute ischemic stroke patients from 36 Japanese hospitals: risk-

adjusted economic and clinical outcomes. International Journal of Stroke. 2011; 6(1):16-24. 5. Evaluation of resource allocation and supply-demand balance in clinical practice with high-cost

technologies. The Journal of Evaluation in Clinical Practice (in press)

Healthcare Economics and Quality ManagementProfessor : Yuichi Imanaka Assistant Professor : Hiroshi Ikai, Tetsuya Otsubo TEL : +81-75-753-4454 FAX : +81-75-753-4455 e-mail : [email protected] URL : http://med-econ.umin.ac.jp/


- Public Health - Health Administration


As a department of School of Public Health (SPH), education and training of professionals who can work in new fields are performed. Investigation of the related academic fields is simultaneously intensively done. Training of (1) professionals for medical ethics committees and (2) Certificated Genetic Counselors (CGC) are especially focused. The CGC system began in 2005 in Japan. New course for genetic counselors and clinical research coordinators started in 2006 related with our department. These fields are expected to increase their need a lot, along with development of advanced medicine and increase in information of genome.

Shinji Kosugi, M.D., Ph.D.Professor

Research and EducationEducation:■ Basic Medical Ethics■ Medical Ethics■ Fundamental human genetics■ Clinical Genetics and Genetic Counseling■ Genetic Medicine and Ethics■ Genetic Medicine and Society

Research Subject:■ Study on ethics committee and ethical evaluation of research plans.■ Study on how genetic medicine should be.■ Study on gene diagnosis and informed consent for genome research.

Recent Publications1. Jin ZB, Mandai M, Yokota T, Higuchi K, Ohmori K, Ohtsuki F, TakakuraS, Itabashi T, Wada Y,

Akimoto M, Ooto S, Suzuki T, Hirami Y, Ikeda H,Kawagoe N, Oishi A, Ichiyama S, Takahashi M, Yoshimura N, Kosugi S. Identifying pathogenic genetic background of simplex or multiplex retinitis

2. Kei Kano, Saiko Yahata, Kaori Muroi, Masahiro Kawakami, Mari Tomoda,KoichiMiyaki, Takeo Nakayama, Shinji Kosugi, Kazuto Kato. Multimedia Presentations on the Human Genome: implementation and assessment of ateaching program for the introduction to genome science using a poster and animations. Biochem Mol Biol Edu. 2008, 36:395-401

3. Yamano E, Isowa T, Nakano Y, Matsuda F, Hashimoto-Tamaoki T, Ohira H, Kosugi S. Association study between reward dependence temperament and a polymorphism in the phenylethanolamine N-methyltransferase gene in aJapanese female population. Comprehensive Psychiatry 2008 49:503-507.

4. Szinnai G, Kosugi S, Derrien C, Lucidarme N, David V, Czernichow P, Polak M: Extending the clinical heterogeneity of iodide transport defect (ITD): A novel mutation R124H of the sodium/iodide symporter (NIS) gene and review of genotype-phenotype correlations in ITD. J Clin Endocrinol Metab,2006 Apr;91(4):1199-204. Epub 2006 Jan 17.

5. Fujita M, Akabayashi A, Slingsby BT, Kosugi S, Fujimoto Y, Tnaka K: A model of donors’ decision-making in adult-to-adult living donor liver transplantation in Japan: having no choice. Liver Transplantation, 2006 May; 12(5):768-74.

6. Takahashi M, Kikuchi M, Ohkura N, Yaguchi H, Nagamura Y, Ohnami S, Ushiama M, Yoshida T, Sugano K, Iwama T, Kosugi S, Tsukada T. Detection of APC gene deletion by double competitive polymerase chain reaction in patients with familial adenomatous polyposis. Int J Oncol. 2006 Aug;29(2):413-21.

7. Itai K, Asai A, Tsuchiya Y, Onishi M, Kosugi S. How do bioethics teachers in Japan cope with ethical disagreement among healthcare university students in the classroom? A survey on educators in charge. J Med Ethics. 2006 May;32(5):303-8.

❶ Staffs ❷ Small Group

Discussion

Medical Ethics/Medical GeneticsProfessor : Shinji Kosugi Associate Professor : Hironao Numabe Assistant Professor : Yuri Dowa TEL : +81-75-753-4647 FAX : +81-75-753-4649 e-mail : [email protected]

Medical Ethics / Medical Genetics

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In today’s society, the impact of health-related information on human behavior and health can be just as profound as, or in some cases, more profound than, the impact of physical environment on human health. This field of study explores how information can contribute to improving people’s health behavior/health-care-seeking behavior, and decision-making in community health. The main topics to be covered are: Evidence-based healthcare (EBHC); decision analysis, health literacy & communication; epidemiologic research including genome approach, quantitative and qualitative assessment of health-related information; e-Health; and information ethics.

Takeo Nakayama, M.D., Ph.D.Professor

Research and EducationResearch and Education Epidemiology (required): Epidemiology is the study of the distribution of illness in populations and its application to the control of health problems. This course will provide students with the fundamental ideas about methodologies and principles of epidemiology. Literature Search (elective): This course serves as an introduction to literature search using some of the largest databases for citations and abstracts from medical literature, such as PubMed, The Cochrane Library, and the web of Japan Medical Abstracts Society. Critical Appraisal (elective): This course will explore not only how to examine but also how to use a range of health-related information based on the knowledge of epidemiology and evidence-based medicine (EBM). Health Informatics (elective): This course will explore how to collect, store, communicate, retrieve, and evaluate health-related information and data. From the point of view of epidemiology and EBM, this course will consider how health-related information from various sources may differ from each other and how such information can be used in an effective and constructive way. Issues related to information literacy, information sharing, and information ethics will also be addressed. Lecture and discussion on the status quo of advanced medicine and a hospital tour will be provided in collaboration with the department of clinical medicine. analysis of epidemiologic data (elective): This course offers the opportunity to analyze real epidemiologic data.

Recent Publications1. Takahashi Y, et al. Potential benefits and harms of a peer support social network service on the

Internet for people with depressive tendencies: qualitative content analysis and social network analysis. Journal of Medical Internet Research. 2009;11:e29

2. Tanaka Y, Nakayama T, Nishimori M, Sato Y. Lidocaine for preventing post-operative sore throat. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD004081

3. Nagai S, et al. Earlier versus later continuous Kangaroo Mother Care (KMC) for stable low-birth-weight infants: a randomized controlled trial. Acta Paediatrica. 2010 Jan 27. [Epub ahead of print]

4. Nakaoka S, et al. Adherence in performing echocardiography to detect valvulopathy associated with the use of ergot-derived dopamine agonists in patients with Parkinson’s disease. Internal Medicine. (in press)

5. Mori H, et al. Characteristics of caregiver perceptions of end-of-life caregiving experiences in cancer survivorship: in-depth interview study. Psycho-oncology. (in press)

(selected)

Health InformaticsProfessor : Takeo Nakayama Associate Professor : Tatsuro Ishizaki TEL : +81-75-753-9477 FAX : +81-75-753-9478 e-mail : [email protected] URL : http://www.healthim.umin.jp/

Health Informatics



Medical Communication is a specialized area in medicine within science communication, which is currently enjoying national and international public attention. Kyoto University is the first in Japan to have established a department of Medical Communication that investigates how medical knowledge is shared and circulated among different societal segments (eg., the public, media, policy makers, and the medical community) on a variety of levels (personal/micro, community/meso, social/macro, and international). Medical communication, therefore, is not the same as health communication, which is a well-known communication field researching a doctor-patient interaction, as the former has a more macro research domain. This new department welcomes students who are eager to not only tackle the aforementioned ambitious theme but also explore and claim the emerging field of medical communication.

Research and EducationFirst semester: In this semester, the course provides an introduction to medical communication, both its theoretical frameworks and applications, for those from diverse interests, backgrounds, and /o r d i sc ip l ines . In c l a s s , f r ames f rom communication studies, disability studies, and/or science communication are drawn, and an issue of communication channels is addressed. Second semester: Building upon the first semester, the course further explores current topics in medical communication, especially relations among the medical/research community, media, public, and policy makers.Below are the course objectives:

●understand frameworks, theories, and concepts that are relevant to medical communication●begin to see a “niche” of your interest in a field of medical communication and find a research question to be explored●understand the interconnectedness among the medical community, media, public (including the stakeholders or interest groups), and policy makers●write a succinct literature review on your topic with a critical perspective

Any research reflects a researcher’s personal history and perspective, and my research has ranged from intercultural communication, health communication, to disability studies. Although they may not seem related, I’ve always been fascinated by the world according to a minority perspective and conducted a series of research projects aimed at investigating people on the margins of society. Within medical communication, I’m interested in such topics as bridging between the medical community and public, aging with disability, and emancipatory research. You may wonder “what do I become by studying medical communication?” I offer you this analogy: doing a rigorous study is similar to getting a road-map on an unknown terrain. This means that the map can help you “read” a targeted landscape or calculate the shortest distance to the goal. Nevertheless, let me remind you, the map itself never tells you which goal to reach or what route to take. It’s all up to you, either you “cut to the chase” to the goal or are sidetracked by attractive views alongside of the scholastic endeavor. I suggest that YOU design a research path of your own through exploring a “map” of medical communication.

Recent Publications1. Iwakuma, M. (2007). A chronicle of my education and disability transformation. In M. L. Vance

(Ed.), Multiple Voices and Identities in Higher Education: Writings by Disabled Faculty and Staff in a Disabling Society (pp. 87-95). Huntsville, NC: Associates on Higher Education And Disability.

2. Iwakuma, M., & Stadnyk, R. (2007). Aging with spinal cord injury, future directions, and implications. In Festival of International Conferences on Caregiving, Disability, and Aging and Technology Proceedings (CD-Rom).

3. Iwakuma, M. (2007). Communication with the elderly and people with disabilities [in Japanese]. In M. Isa (Ed.), Multi-cultural Society and Intercultural Communication (2nd Edition). Tokyo: Sanshu Press.

4. Iwakuma, M (2005). A transformation: A disability adjustment through communication [in Japanese]. In Sakai Ikuko (Ed.), Transcendental rehabilitation (pp. 12-21). Tokyo: Bunkodo.

5. Iwakuma, M. (2003). Being Disabled in Modern Japan: A Minority Perspective. In E. M. Kramer (Ed.), The Emerging Monoculture: “Model Minorities” and Benevolent Assimilation (pp. 124-138). Praeger Press.

Medical CommunicationAssociate Professor : Miho Iwakuma, Ph.D. TEL : +81-75-753-4668 e-mail : [email protected]

Medical Communication



Along with paradigm change taking place on global scale, universities are counted upon by the public on their capability in handling these changes. Under much expectations from both industry and government sector, universities now have a role to contribute to society by leading the development of advanced scientific technologies from basic research to industrially applicable form.The department aims to foster managers of intellectual property in order to promote technology transfer in life science.

Hirokazu YAMAMOTO, Ph.D.Professor

Research and EducationAs well as equipping students with practical skills, the department teaches basic theories particularly in the field of advanced medicine, IP low and business particularly on the exploitation of intellectual property rights. The department aims to nurture directors of technology management, the personnel with the capability to discover, manage and exploit the intellectual property in the field of biotechnology, particularly in advanced medicine.

1.Medical Science: the department will give students top-level scientific knowledge and the knowledge on industrial demand through lectures by the academics who are engaged in researches of forefront science at the graduate school of medicine, and by the industrial professionals who hold abundant experience in translational research and development research in the industry.

2.IP Law and Business: the department will give students basic knowledge of intellectual property laws and life science industry through lectures by instructors selected for each specialization field. The practical skills and knowledge in accounting and market valuation and distribution of intellectual property are taught through lectures by lecturer with a long career in business such as venture capital.

3.Practical Skills: Using the knowledge learned above as a base, the department will equip students with ability to act in real situation through work experience at Kyoto University and through other externships, gaining experience in establishing rights in research out come and in exploitation of those rights.

At the Management of Technology and Intellectual Property, we are being conducted on various problems faced in management and practical application of intellectual property rights. So far, research has been conducted on “Investigation for protection and utilization of intellectual property in translational research for purpose of establishing the management system” and “Systems of intellectual property management which can accommodate movement of researchers from one institution to another”. The findings from these researches are reflected in the management of intellectual property at Kyoto University.

Recent Publications1. Chikako SAOTOME “Investigation of Access to Research Materials in Life Science” Intellectual

Property Association of Japan, 2010.6 2. Hideho TANAKA, Kiyohide NAGAOKA, Katsuhiro INAMURA “Supply and Use of Intellectual

Capital in High-Tech Startups” Intellectual Property Association of Japan, 2010.6 3. Kiyohide NAGAOKA, Katsuhiro INAMURA, Hideho TANAKA “Supply and Use of Intellectual

Property by High-Tech Startups : Comparative Business Analysis” Intellectual Property Association of Japan, 2010.6

4. Chikako Saotome, Hideho Tanaka “Management of Medical Intellectual Property and Publication at Universities” Journal of Healthcare and Society, Vol.20, No.2, 155-167, 2010

❶ Members ❷ Ent repreneursh ip

Exercise ❸ Ent repreneursh ip

Exercise Members

Management of Technology and Intellectual PropertyProfessor : Hirokazu Yamamoto Professor (Special Appointment) : Yutaka teranishi Professor : Seiji Abe Associate Professor : Chikako Saotome Part-time Lecturer : Ken-ichi Kumagai, Hideho Tanaka, Atsushi Fujii Assistant Professor : Tomochika Aono TEL : +81-75-753-9332 FAX : +81-75-753-9333 e-mail : [email protected] URL : http://www.motkyoto.com

Management of Technology and Intellectual Property

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- Public health - Health Administration


Our proximate goal is to analyze gene-environmental interactions for development of adverse health effects. As environmental factors, persistent organic pollutants, nutrition and working conditions are within our research scope. Laboratory works, genetic epidemiology and field studies are routinely used to solve the problems. Our long-term goal is to practice preventive measures based on our findings. Candidates with public health mind, from any disciplines, will be welcome.

Akio Koizumi, M.D., Ph.D.Professor

Research and EducationWe are exposed to various health hazards. These are found in routine life styles, diets, environmental pollutants and occupational settings. To build rational preventive measures, both susceptive genetic determinants and environmental factors should be taken into account. When our global environment was clean, a phenotype susceptible to dioxins or to formaldehyde had never emerged as a public health issue. However, as our environment is contaminated with chemicals, phenotypes associated with chemical exposures have emerged as an important public health issue: for example formaldehyde causes asthma in some people while it does not in others. In short, changes in environment always have revealed new phenotypes and brought new public health issues. We therefore consider it critical to dissect gene-environmental interactions in a dynamic state. On this basis, we would like to conduct public health practices. Currently, following projects are ongoing. The first one is to find susceptible genes for Moyamoya disease (figures). We have also analyzed in our laboratory from a viewpoint of preventive medicine against brain infarction and breeding in the childhood. In the second project, we are assessing levels of exposure to persistent organic pollutants in a 30-year span. In this project, we are building the Environmental Sample Bank which is open to the public. In parallel we are investigating pharmacological act ions of organofluorine compounds at molecular levels. In the last project, we are working on chronic kidney disease (CKD) in Sri Lanka. In this project we are investigating the mechanism and the prevention of CKD. We have still other ongoing projects related to common diseases such as diabetes.

Recent Publications1. Fujii Y et al., Detection of dicofol and related pesticides in human breast milk from China, Korea

and Japan. Chemosphere 2011, 82:25-31 2. Chandrajith R, Nanayakkara S et al., Chronic kidney diseases of uncertain etiology (CKDue)

in Sri Lanka: geographic distribution and environmental implications. Environ Geochem Health 2011:DOI: 10.1007/s10653-10010-19339-10651

3. Liu W et al., A rare Asian founder polymorphism of Raptor may explain the high prevalence of Moyamoya disease among East Asians and its low prevalence among Caucasians. Environ Health Prev Med 2010, 15:94-104

4. Hashikata H et al., Confirmation of an association of single-nucleotide polymorphism rs1333040 on 9p21 with familial and sporadic intracranial aneurysms in Japanese patients. Stroke 2010, 41:1138-1144

5. Niisoe T et al., Long-Term Simulation of Human Exposure to Atmospheric Perfluorooctanoic Acid (PFOA) and Perfluorooctanoate (PFO) in the Osaka Urban Area, Japan. Environ Sci Technol 2010, 44:7852-7857

6. Inoue K et al., Search on chromosome 17 centromere reveals TNFRSF13B as a susceptibility gene for intracranial aneurysm: a preliminary study. Circulation 2006, 113:2002-2010

❶ Our members ❷ Normal (left) and Moyamoya vessels

(right) ❸ Pedigrees of genetic analysis of

familial Moyamoya disease ❹ Atmospheric simulation of lead in

East Asia ❺ Field work of CKD in Sri Lanka

Health and Environmental ScienicesProfessor : Akio Koizumi Associate Professor : Kouji Harada Lecturer : Toshiaki Hitomi Assistant Professor : Kokoro Iwasawa Research Associate : Tamon Niisoe JSPS Post Doctoral Fellow : Hatasu Kobayashi JSPS Post Docoral Fellow for Foreign Researcher : Liu Wangyang Researcher : Senevirathna Lalantha TEL : +81-75-753-4456 FAX : +81-75-753-4458 e-mail : [email protected] [email protected].

kyoto-u.ac.jp URL : http://hes.med.kyoto-u.ac.jp/


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- Public Health - Health Determinants


Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine / School of Public Health, promotes pragmatic and empirical research on behaviors and cognitions that bear on disease and health of humankind. Its two vehicles of research consist of cognitive-behavior therapy (CBT) and clinical epidemiology (evidence-based medicine: EBM). CBT offers skills to produce changes in health-related behaviors and cognitions, while EBM provides solid methodology to evaluate their effectiveness and to disseminate proven skills in the real world.

Toshiaki A. Furukawa, MD, PhDProfessor

Research and EducationThe research themes in the Department currently include:1. In the field of CBT,1.1. Research and development of new CBT programs for anxiety disorders, mood disorders and psychotic disorders1.2. Research and development of CBT programs for patients with physical diseases1.3. Research and development of CBT programs applicable to workplace and school1.4. Research and development of methods to teach and disseminate CBT2. In the field of EBM,2.1. Network meta-analyses of psychosocial and biological therapies for depression (in collaboration with the Cochrane Collaboration Depression, Anxiety and Neurosis Group)2.2. Research and development of new methods to translate evidence into clinical practices, applying epidemiology, statistics and psychometrics.2 . 3 . A p r a g m a t i c m e g a - t r i a l t o e s t a b l i s h optimum treatment strategies of new generation antidepressants for major depressionWe further plan to run the following workshops in the near future.3. Hands-On Workshop on How to Utilize EBM in your Busy Clinic4. Workshops on How to Complete Systematic Reviews (Meta-analyses)5. Introductory, Intermediate and Advanced Workshops for CBT

The Department is also a collaborator for the Master of Clinical Research program.

For those who wish to study with us:We expect our MSc and PhD students to actively take part in one of our on-going research projects.

Recent Publications1. Furukawa, T. A., McGuire, H., Barbui, C. (2002) Meta-analysis of effects and side-effects of low

dosage tricyclic antidepressants for depression: systematic review. BMJ 325: 991-995. 2. Geddes, J. R., Carney, S. M., Davies, C., Furukawa, T. A. et al (2003). Relapse prevention with

antidepressant drug treatment in depressive disorders. Lancet 361: 653-661. 3. Otsu, A., Araki, S., Sakai, R. et al (2004) Effects of urbanization, economic development and

migration of workers on suicide mortality in Japan. Social Science & Medicine 58, 1137-1146. 4. Furukawa, T. A., Watanabe, N., Omori, I. M. et al (2007) Association between unreported

outcomes and effect size estimates in Cochrane meta-analyses. JAMA, 297, 468-470. 5. Cipriani, A., Furukawa, T. A., Salanti, G. et al (2009) Comparative efficacy and acceptability of 12

new-generation antidepressants: a multiple-treatments meta-analysis. Lancet, 373, 746-758. BooksFurukawa, T. “Evidence-Based Psychiatry: From Theory to Practice” Igaku-Shoin, 2000.Furukawa, T. “Cognitive-Behavior Therapy Live Sessions by A. T. Beck and J. Beck” Igaku-Shoin,

2008.Furukawa, T. A., Jaeschke, R., Cook, D. Guyatt, G. (2008) Measurement of Patients' Experience. In

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice (2nd edn), pp. 249-271. New York: The McGraw-Hill Companies, Inc.

Health Promotion and Behavior ScienceProfessor : Toshiaki A. Furukawa, MD, PhD Associate Professor : Akiko Yamasaki, MD, PhD TEL : +81-75-753-9491 FAX : +81-75-753-4641 e-mail : [email protected] URL : http://ebmh.med.kyoto-u.ac.jp

Health Promotion and Human Behavior



Caring for the ill persons is the origin of medicine. Prevention of disease is another matter of importance. Prevention includes preventing the occurrence of a disease (primary prevention) and arresting the progression of a disease through early diagnosis and early treatment (secondary prevention). Kyoto University Health Service is the primary-care facility for preventive services, such as health checkups and promotion, for students and employees of Kyoto University. We also provide health guidance and counseling as well as primary care for diseases and injuries. In our practice, we conduct epidemiological research for disease control and prevention, and develop various healthcare systems. In this way, we disseminate evidence from the on-site daily clinical routine.

Takashi Kawamura, M.D., Ph.D.Professor

Research and Education“Sudden death of employees frequently occurs in April and on weekends.” “Water-gargling prevents common cold.” ”Chest compression-only resuscitation is the best way for lay bystanders.” “Introduction of hemodialysis in IgA nephropathy can be predicted by blood pressure, urine protein, urine blood, serum albumin, etc.” ”Adverse events of gefitinib are more common among patients with some characteristics.” We are studying quite common health problems to contribute to daily healthcare. Our study tool is epidemiology. We collaborate with many medical and governmental facilities all over the country.In the School of Public Health, we participate in a core-course on “Epidemiology” which helps us to evaluate the causes of a disease and the effectiveness of medical procedures through observation and intervention, and also in courses on ”Study protocol writing and study management” and ”Cardinal points in clinical research practice” for students who intend to carry out clinical researches. We continuously mentor each student assigned to our department. As a graduate school student, some medical qualifications are required because we study in practices. See the webpage of the University Health Service.

Recent Publications1. Kawamura T, Kondo H, Hirai M, et al. Sudden death in the working population: a collaborative

study in central Japan. Eur Heart J 1999; 20: 338-343. 2. Satomura K, Kitamura T, Kawamura T, et al. Prevention of upper respiratory tract infections by

gargling: a randomized trial. Am J Prev Med 2005; 29: 302-307. 3. Iwami T, Kawamura T, Hiraide A, et al. Effectiveness of bystander-initiated cardiac-only

resuscitation for patients with out-of-hospital cardiac arrest. Circulation 2007; 116: 2900-2907. 4. Goto M, Kawamura T, Ando M, et al. A scoring system to predict renal outcome in IgA

nephropathy: a nationwide 10-year prospective cohort study. Nephrol Dial Transplant 2009; 24: 3068-3074.

5. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small cell lung cancer patients treated with gefitinib. J Clin Oncol 2006; 24: 2549-2556.

❶ Randomized controlled t r ia l evaluat ing the preventive effect of gargling for common cold (Ref No.2)

❷ Patients cohort study ident i fy ing the r isk fac to rs o f adverse events by gefitinib (Ref No.5)

Preventive ServicesProfessor : Takashi Kawamura Associate Professor : Kazumi Takemoto, Masahiko Ando Senior Lecturer : Masashi Goto Assistant Professor : Taku Iwami, Teruhisa Uwatoko TEL : +81-75-753-2400 FAX : +81-75-753-2424 e-mail : [email protected] URL : http://www.kyoto-u.ac.jp/health/kuhc-

home.html

Preventive Services

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“Socio-epidemiology” is a new methodological approach for the New Public Health. Integrating sociological and epidemiological perspectives and methodologies, it takes a multidisciplinary approach encompassing epidemiology, biostatistics, mixed method, social marketing, behavioral science, and communication science. Utilizing this novel approach while following the tradition of Kyoto University that appreciates field-based rather than “arm-chair” activities, we value the practice in the field and contextual understanding of people, explore the solutions that are both scientific and socio-culturally appropriate, and thus aim to contribute to the improvement of global health. With successful application of this approach to the field of HIV/STDs epidemiology and prevention in Japan as well as abroad over the last decade, our department has been designated as the first Collaborating Centre of the UNAIDS since 2006. Masahiro Kihara, M.D., Ph.D.

Professor

Research and EducationOur major research projects include the WYSH Project (Well-being of Youth in Social Happiness) in Japan and the HADI Project (HIV/AIDS Prevention Studies among Drug Users in Iran) in Iran. WYSH Project is an HIV/STDs education project for youth, created through socio-epidemiological approach in 2003. Having been proven highly effective in improving knowledge, attitude and behaviors, it has evolved into the largest project of its kind in Japan and was adopted as a national project by the Ministry of Education, Culture, Sports, Science and Technology in 2007. The HADI Project has started in 2003 with a socio-epidemiological study that first described the HIV epidemic among injecting drug users (IDUs) in Iran and identified needle/syringe sharing practice during incarceration as a major risk factor for HIV infection. Our further studies showed the effectiveness of needle/syringe exchange program in the community and the methadone maintenance treatment in prison, having had a strong impact on shaping the national HIV prevention programs of Iran. Other research activities include HIV/STDs-related behavior surveys in Japan as well as in many developing countries including China, Thailand, Bangladesh, Nepal, and Burkina Faso. Education and mentoring activitiesEducation activities are focused on the systematic teaching of socio-epidemiology. In the first semester, students learn the theoretical basis of socio-epidemiology; how multiple methodologies and/or concepts including quantitative method, qualitative method, behavioral science, communication science, and social marketing, are integrated to reach deep contextual understanding of the people and to create effective and socio-culturally appropriate prevention programs. In the second semester, students will be given a series of lectures and practicum on qualitative methods including focus group interviews, and various types of qualitative data analysis and on the theories and skills of questionnaire development. Throughout this course students are expected to acquire enough knowledge, skills and mindset to plan and implement socio-epidemiological programs. Our department is also responsible for the education of infectious disease epidemiology, including the topics such as emerging and re-emerging infectious diseases, mathematical modeling of infectious disease epidemics, and field epidemiology. Students of our department were/are from various countries that include Iran, China, Zambia, Myanmar, Bangladesh, Nepal, Peru, Democratic Republic of Congo, Thailand, Swaziland and Yemen.

UNAIDS Collaborating CentreOffice of the UNAIDS Collaborating Centre for Socio-epidemiological HIV Research is placed in our department. Activities of the centre include research, training, communication and networking.

Recent Publications1. Ono-Kihara M, Sato T, et al. Demographic and behavioral characteristics of non-sex worker

females attending sexually transmitted disease clinics in Japan: a nationwide case-control study. BMC Public Health. (2010) 10:106

2. Zamani S, Ono-Kihara M, et al. Potential for sexual transmission of HIV infection from male injecting-drug users who have sex with men in Tehran, Iran. Sex Transm Dis. 2010 [Epub ahead of print]

3. Zamani S, Radfar R, et al. Prevalence of HIV/HCV/HBV infections and drug-related risk behaviours amongst IDUs recruited through peer-driven sampling in Iran. Int J Drug Policy. 2010 [Epub ahead of print]

4. Zamani S, Farnia M, et al. Patterns of drug use and HIV-related risk behaviors among incarcerated people in a prison in Iran. J Urban Health. 2010 Jul;87(4):603-16.

5. Zamani S, Farnia M, Tavakoli S, Gholizadeh M, Nazari M, Seddighi AA, Setayesh H, Afshar P, Kihara M. A qualitative inquiry into methadone maintenance treatment for opioid-dependent prisoners in Tehran, Iran. Int J Drug Policy. (2009) Apr 21. [Epub ahead of print]

6. Ma Q, Ono-Kihara M, Cong L, Xu G, Pan X, Zamani S, Ravari SM, Zhang D, Homma T, Kihara M. Early initiation of sexual activity: a risk factor for sexually transmitted diseases, HIV infection, and unwanted pregnancy among university students in China. BMC Public Health. (2009) Apr 22;9:111.PMID: 19383171

7. Hoque HE, Ono-Kihara M, Zamani S, Ravari SM, Kihara M. HIV-related risk behaviours and the correlates among rickshaw pullers of Kamrangirchar, Dhaka, Bangladesh: a cross-sectional study using probability sampling. BMC Public Health. (2009) Mar 11;9:80.PMID: 19284569

8. Homma T, Ono-Kihara M, Zamani S, Nishimura YH, Kobori E, Hidaka Y, Ravari SM, Kihara M. Demographic and behavioral characteristics of male sexually transmitted disease patients in Japan: A nationwide case-control study. Sex Transm Dis (2008) Oct 2. [Epub ahead of print]

❶ Opening ceremony for UNAIDS Collaborating Centre (2006, Kyoto) and the plate for the centre

❷ Socio-epidemiological study on the risk behaviors of rickshaw pullers in Bangladesh (2008)

❸ Socio-epidemiological studies on injecting drug users in Iran (2003 ) ❹ National Training Course for the WYSH Project by MEXT (2009)

Global Health and Socio-epidemiologyProfessor : Masahiro Kihara, MD, PhD Associate Professor : Masako Ono-Kihara, Ph.D. (Director of the UNAIDS

Collaborating Centre) TEL : +81-75-753-4350 FAX : +81-75-753-4359 e-mail : [email protected]


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- Public Health - International Health


Japan has attained the high life expectancy and low infant death rate which we can be proud of. Based on a historical viewpoint, we study the public health and the health policy of Japan supporting this life expectancy and healthy life style, and are targeting to contribute to the development of a future healthy policy. We also carry out research on the global health policy by WHO etc. The basic knowledge of the public health is necessary for the further study on Japanese health policy. For such reasons, we would like researchers with enough knowledge on general medicine and/or the public health system of the country and fluent English speaking faculty.

Toshitaka Nakahara, M.D., PH.D., M.P.H.Professor

Research and EducationOur department is the Public Health in Faculty of Medicine and the Public Health and International Health in the School of Public Health. In education, we are carrying out several programs, such as the “public health” lectures in the Faculty of Medicine and the School of Health Science, “community nursing” in the School of Health Science and core-curriculum, “health policy” and “international health” in the School of Public Health. Being based on a historical viewpoint of healthy political science and by using the qualitative and quantitative analysis method and/or its fusion-technique, and the social-marketing-technique, we investigate the current situation and the most effective health policies. The tobacco control measures are important subjects not only in Japan but also in the global, and we are advancing these topics positively. We also give lectures at conferences in abroad on the preventable smoking measures. In the field of international health, we collect the information on the international systems including WHO, and compare them with those of Japan etc. Now, besides the research on health policies of Japan, we study laws and regulations regarding public health. Also, we study and compare food safety measures including measures, against terrorism in Japan and foreign countries.

Recent Publications1. Current Japanese Tobbacco Consumption Situation. Toshitaka Nakahara, K. Satomura, S.

Iwanaga, R. Sakamoto, M. Noami, T. Takahashi Tobacco Counters Health, Volume 4, ISBN 81-7211-208-4, P.11-13 2005

2. Hospital's Measures against Passive Smoking. Ryota Sakamoto, Toshitaka Nakahara, Kazunari Satomura, Suketaka Iwanaga, Megumi Noami, Akihiko Kinugasa Tobacco Counters Health, Volume 4, ISBN 81-7211-208-4, P.23-27 2005

3. What is Necessary to Obey the FCTC in Japan. Kazunari Satomura, Toshitaka Nakahara, Suketaka Iwanaga, Ryota Sakamoto, Megumi Noami, Toru Takahashi Tobacco Counters Health, Volume 4, ISBN 81-7211-208-4, P.32-35 2005

4. Changes of Health Warning Labellings on Japanese Tobacco Packages Suketaka Iwanaga, Toshitaka Nakahara, Kazunari Satomura, Ryota Sakamoto, Megumi Nomai, Toru Takahashi

Tobacco Counters Health, Volume 4, ISBN 81-7211-208-4, P.36-38 2005 5. New approaches to public health education, research and practice Toshitaka Nakahara, Raku-Yu 10

4-5 2006 6. Takashi Muto, Toshitaka Nakahara, Eun Woo Nam : Asian Perspectives and Evidence on Health

Promotion and Education. Springer 2011

❶ The 7th Annual Meeting of International Society for the Prevention of Tobacco Induced Diseases

❷ Staff

Public Health and International HealthProfessor : Toshitaka Nakahara Associate Professor : Kazunari Satomura Assistant Professor : Suketaka Iwanaga TEL : +81-75-753-4465 FAX : +81-75-753-4466 e-mail : [email protected]

Public Health and International Health

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- Public Health - International Health


Of the risk factors that are distributed in the environment and influence human health pathogenic microorganisms are important. Various factors affect the process where pathogenic microorganisms in the environment cause infections. The factors in the natural environment influence the survival and propagation of pathogenic microorganisms. Socioeconomic factors in the human-life environment have effects on the contact between pathogens and humans, resistance of individuals as well as the community, and so on and thus greatly affect the emergence of infectious diseases. In addition, these factors may influence each other. We analyze how various factors interact with individual pathogen and the infection using an ecological approach.

Mitsuaki Nishibuchi, Ph.D.Professor

Research and EducationWe try to guide graduate students so that they can learn the approach for comprehensive analysis of various factors including the natural environment where pathogens persist, the human environment, the resistance of humans as the host of pathogens in order to understand emergence and transmission of infectious diseases. We carry out studies in Thailand, Malaysia, Vietnam, India , Bangladesh, and China in collaboration with local researchers. We isolate Vibrio cholerae, Vibrio parahaemolyticus, and Escherichia coli O157 from the environmental and clinical specimens and analyze the isolated strains. We investigate the factors affecting the emergence of infectious diseases by comparative and comprehensive analysis of the isolated bacteria and the environmental and clinical data. We also study the infectious diseases that are not restricted to a country or an area but are spread across international borders. We determine and compare the phenotypic and genetic characters of the strains isolated in various areas to clarify their phylogenetic relationships to understand the epidemiology of infectious diseases. Investigation of the relationship between the phylogenetic relationship of the strains and international movement of humans and commodities will allow us to reveal the factors involved in transmission of infectious diseases. For example, contamination of food materials by the pathogens in the natural environment becomes a risk factor for local people as well as the threat to the people in other parts of the world. However, incidence of infections may differ considerably from area to area. If we include analysis of these observations, the study starting at a “micro” level can be expanded to cover the investigation of infectious diseases at a “macro” level.

Recent Publications1. Nakaguchi, Y., and M. Nishibuchi. 2005. The promoter region rather than its downstream inverted

repeat sequence is responsible for low-level transcription of the thermostable direct hemolysin-related hemolysin (trh) gene of Vibrio parahaemolyticus. J. Bacteriol. 187(5):1849-1855.

2. Koitabashi, T., V. Vuddhakul, S. Radu, T. Morigaki, N. Asai, Y. Nakaguchi, and M. Nishibuchi. 2006. Genetic characterization of Escherichia coli O157:H7/- strains carrying the stx2 gene but not producing Shiga toxin 2. Microbiol. Immunol. 50(2): 135-148.

3. Koitabashi, T., S. Cui, K. Muhammad, and M. Nishibuchi. 2008. Isolation and characterization of the Shiga toxin gene (stx)-bearing Escherichia coli O157 and non-O157 from retail meats in Shandong Province, China and characterization of the O157-derived stx2 phages. J. Food Prot. 71(4):706-713.

❶ Environmental survey to assess the risk of Vibrio parahaemolyticus in bloody clams in Thailand

❷ I n t e r v i e w t o e x a m i n e t h e relationship between the incidence of diarrhea and socioeconomic factors in Vietnam

❸ We developed a quick and easy genetic method to identify the new clone of V. parahaemolyticus responsible for pandemic spread of infection. This method has been used by many workers in various parts of the world


Ecology with Emphasis on the EnvironmentCenter for Southeast Asian StudiesProfessor : Mitsuaki Nishibuchi TEL : +81-75-753-4442 FAX : +81-75-753-7350 e-mail : [email protected] URL : http://www.cseas.kyoto-u.ac.jp/index_

ja.htm

Ecology with Emphasis on the Environment Division of Integrated Area Studies

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- Public Health - Center for Southeast Asian Studies


Modern clinical (bed-side) medicine have much succeeded in the lifesaving of the patients with acute diseases. As the results now, aging population have developed not only developed countries but also developing countries. However, modern clinical medicine in the hospital cannot completely deal with community-dwelling frail elderly patients with several chronic conditions living in each different ecology and socio-economical situation. Field medicine is addressing the comprehensive geriatric issues of community-dwelling elderly in the world using comprehensive geriatric assessment through actual medical field works.

Kozo Matsubayashi, M.D., Ph.D.Professor

Research and EducationWorking issues of our field medical teams are below.

(1) Comprehensive geriatric assessment and community-based intervention for the community-dwelling elderly in Japan.Comprehens ive ge r i a t r i c a s s e s smen t and community-based intervention for the community-dwelling elderly have been carried out in Kahoku and Tosa in Kochi, Sonobe in Kyoto, Yogo in Shiga and Urausu in Hokkaido.

(2) Comprehensive geriatric assessment for the community-dwelling elderly in Asia.Cross-sectional comprehensive geriatric assessment for the community-dwelling elderly have been carried out in Korea, West Java in Indonesia, Vietnam, Laos and Myanmar.

(3) Medical research for nerurodegenerative diseases in West Papua.We have carried out medical field research f o r a m y o t r o p h i c l a t e r a l s c l e r o s i s a n d Parkinson·Demantia complex disease in West Papua (Irianjaya) in Indonesia detecting some above patients. Future study is needed for etiological assessment.

Recent Publications1. Matsubayashi K et al. Mood Disorders in the Community-Dwelling Elderly in Asia. J Am Geriatr

Soc, 58 (1);213-214, 2010. 2. Matsubayashi K et al. ,Changing attitudes of elderly Japanese toward disease. J Am Geriatr Soc.

57 (9), 1732-1733, 2009. 3. Kimura Y et al. Comprehensive geriatric assessment of elderly highlanders in Qinghai, China IV:

Comparison of food diversity and its relation to health of Han and Tibetan elderly. Geriatr Gerontol Int 9 (4):359-365, 2009.

4. Okumiya K et al. Improvement in obesity and glucose tolerance in elderly people after lifestyle exchange 1 year after an oral glucose tolenrance test in a rural area in LAO People’s Democratic Republic. J Am Geriatr Soc 56: 1582-1583, 2008.

5. Fujisawa M et al. Trends in diabetes. Lancet 369:1257, 2007

❶ A scene of CGA in West Java in Indonesia. ❷ Home visit patients living in a house on the tree, in West Papua.

Field Medicine Center for Southeast Asian StudiesProfessor : Kozo Matsubayashi TEL : +81-75-753-7368 FAX : +81-75-753-7168 e-mail : [email protected] URL : http://www.cseas.kyoto-u.ac.jp/

Field Medicine Division of Humans' and the Environment

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- Public Health - Field Medicine - Center for Southeast Asian Studies


The environment is the theme that has been taken up since the time of Nightingale, and is placed as one of the basic concept in nursing science. The environment has various influences on the health of people, but the recognition and relation for the environment have changed according to the state of mental and physical health. Conventionally, the relations between the person and the environment have been discussed in terms of determinism or the interaction theory. However, "Man-Environment System" has become widely accepted.�In our field, we investigate the healthy phenomena in various fields scientifically from the viewpoint of "Man -Environment System" with the aim of building a new domain called the environmental health nursing.

Sawako Suga, C.C.P., Ph.D.Professor

Research and Education The main studies of our stuff are as follows; 1.study of the relationship between living environment and sleep-wake rhythm of home care patients, 2.study about the influence of light environment gives to sleep-wake cycle, and 3.study about the technique of moving and positioning the patient in bed. In addition, 4.study of the nursing counseling, sandplay-drama method story method and mental health of school or the workplace that we store on verbal and nonverbal communication. For study environment, a living environment system laboratory and an interview / developmental assessment room are prepared. In the living environment system laboratory, we can make several study that we experiment of daily life of home care patients or controlled the environmental parameter. In addition, we can enforce counseling, interview and sand play technique in an interview / developmental assessment room.

Recent Publications1. Suga S, Miyajima A, Wakamura T, Suzuki K :Communication in Nursing Care. Igakugeijutsusha,

2009 2. Suga S : Psychology concerning nurse’s interpersonal relationship, Medica,2007 3. Wakamura T: Biological Rhythm and Health Science, Maruzen, 2008 4. Suzuki K, Miyajima A: The trial of nursing education to bring up the health outlook. Annual

Reports of Human Health Sciences Graduate School of Medicine, Kyoto University, 5; 37-41,2008 5. Kubota Y, Takasu NN, Horita S, Kondo M, Shimizu M, Okada T, Wakamura T, Toichi M.,

Dorsolateral prefrontal cortical oxygenation during REM sleep in humans. Brain Res. 2011 Mar 4.

❶ Actgram and sleep-wake analysis of home care patient with Actiwatch ❷ Influences of different light intensities during daytime ❸ Pressure mapping in tilt position ❹ One scene of sandplay-drama method

Environmental Health NursingProfessor : Sawako Suga, C.C.P., Ph.D. Associate Professor : Tomoko Wakamura, R.N., P.H.N., Ph.D. Assistant Professor : Kazuyo Suzuki, R.N., P.H.N., M.A. List for Tel, Fax &E-Mail : See page 000-000

Environmental Health Nursing

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- Basic Nursing Science


Homeostasis has evolved over time as an internal mechanism to protect the body against harmful pathogens such as bacteria and many kinds of physical, chemical and social stressors. Defense functions are one component of homeostasis in living creatures. Human Body Defense and Patho-physiology Nursing Science aims to introduce and discuss (i) infection as one source of body immune reaction, (ii) hospital acquired infection, (iii) mechanisms of body defense and (iv) epidemiology. It also focuses on life factors such as stress which effect reduction of or activation of body defense functions. This course‘s final aim is to establish the new theories for prevention of infection and infection control for immuno-compromised hosts based on a holistic human approach through clinical and laboratory study.

Shinichi Nomoto

Yumi Saito

Research and EducationResearch The focus of clinical study in this course particularly concerns infection prevention for immuno-compromised patients, and their quality of life. Continuous study in the laboratory setting elucidate causative factors of reactivation of infection for the compromised host and the mechanisms of reactivation. The theme of applied studies is development of nursing care for infection prevention in compromised patients by improving their state of stress and their immune function. EducationEducation for undergraduates deals with the concept of Host-Environment Interaction, basic theories of hospital infection control and basic knowledge of immune function. It also covers teaching for laboratory techniques for investigation and identification of bacterial pathogens and blood tests for identifying antibodies as an introduction of Human Body Defense and Patho-physiology Nursing Science.

Recent Publications1. Effectiveness of preferabole color light on psychosomatic state evaluated by emotional parameter

and biochemical parameters. Yumi SAITO, Etsu RA, Satoshi SASAYAMA, Kuniaki SAITO, Hiroki TOYOKAWA

2. Yumi Saito,Satoshi Sasayama, Sawako Suga,Masaki Ikemoto: Effects of Color Images on Psychosomatic State- Effectiveness of Color Images as Mood Stimulants as Assessed by Using an Image Selection System- . Japanese Journal of Complementary and Alternative Medicine Vol.5, p225-232, 2008

3. Yumi Saito, Harue Tada: Effects of color images on stress reduction: Using images as mood stimulants. JANS 4, 1-8, 2007

4. Yumi Saito, Sawako Suga: The Study of the Effectiveness of Color Images on Stress Reduction Health Science 2: 1-7, 2006.( School of Health Sciences, Faculty of Medicine , Kyoto University). 5. Yumi Saito,Keiko Seki,Tomoko Ohara,Chieko Shimauchi,Yoko Honma, Mutsumu Hayashi,Shogo

Masuda,Masayasu Nakano: Epidemiologic Typing of Methicillin-Resistant Staphylococcus aureus in Neonate Intensive Care Unite Using Pulsed-Field Gel Electrophoresis. MICROBIOLOGY and IMMUNOLOGY 42 (11) 1998

❶ Figure 1: Show the results of mean change of biochemical stress parameter, cortisol and chromogranin A after viewing color images. The participants are 20 healthy worker (study group:10 persons, control group:10 persons)

❷ Table 1: Show the results of mean change of biochemical stress parameter, cortisol and chromogranin A and the change of multiple mood score after viewing color images.

Human Body Defense & Patho-physiology Nursing ScienceProfessor : Yumi Saito, RN, MNS, PhD. Shinichi Nomoto, MD, D.Med.Sc. Assistant Professor : Momoe Utsumi List for Tel, Fax& E-Mail : See page 000-000


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- Nursing Science - Basic Nursing Science


As health and social lifestyles have been changing in recent years, lifestyle-related diseases have been increasing, even among younger people, posing important social problems. In this course, you will learn nursing intervention to prevent lifestyle-related diseases and their associated complications. You are expected to obtain knowledge about nursing care/treatment to help patients modify their behavior as well as nursing theories, and thus develop practical skills. You are also expected to cultivate your abilities to improve clinical practices and nursing education, and to review them based on scientific evidence.

Kiminori Hosoda MD. Ph.DKazuko Nin RN. Ph.D

Professor

Research and EducationOur research team is engaged in developing “nursing diagnostic indicators,” “nursing intervention techniques,” and “outcome indicators” for patients with chronic disorders. Specifically, for patients with diabetes to be protected from the development or advancement of complications, we are conducting research on: 1) self-care behavior, 2) nursing diagnosis/intervention for foot care and evaluation of the intervention, and 3) risks for developing foot ulcer in patients with diabetes. For patients with postoperative lymphedema such as those following an operation for uterine cancer, we are undertaking research on 4) nursing diagnosis/intervention for lymphatic drainage. For patients with respiratory or neuromuscular disorders, we are studying 5) nursing diagnosis/intervention for lung physiotherapy (squeezing).Regarding educational activities, we are committed to cultivating the ability to comprehensively understand patients in different stages including the onset of lifestyle-related diseases and their remission, exacerbation, and acute exacerbation. We are also engaged in developing the assessment capability to solve nursing problems in patients with chronic disorders, as well as nursing intervention techniques and the ability to evaluate the intervention. For these purposes, training contents are focused on understanding peripheral theories for nursing diagnosis, acquiring nursing intervention techniques, and analyzing the results. Instructors for our team are working for the outpatient departments at the Kyoto University Hospital. Exploiting these advantages to the full, we provide a curriculum incorporating seminars and practices as well as lectures, thus aiming to nurture competitive clinical nurses and teachers equipped with superior nursing intervention techniques.

Recent Publications1. Sumikawa MD, Egawa T, Honda I, Yamamoto Y, Sumikawa Y, Kubota M (2007) Effects of foot

care intervention including nail drilling combined with topical antifungal application in diabetic patients with onychomycosis. The Journal of Dermatology, 34, 456-464

2. Daitoku M, Egawa T, Fujiwara Y, Okumiya A(2007) Effects of foot care intervention on self-care behavior in the patients with diabetes mellitus. Journal of the Japan Diabetes Society 50(2) p 163-172

3. T. Tanaka, H. Masuzaki, S. Yasue, K. Ebihara, T. Shiuchi, T. Ishii, N. Arai, M. Hirata, H. Yamamoto, T. Hayashi, K. Hosoda, Y. Minokoshi, K. Nakao. Central Melanocortin Signaling Restores Skeletal Muscle AMP-Activated Protein Kinase Phosphorylation in Mice Fed a High-Fat Diet. Cell Metab. 5(5):395-402, 2007

❶ This is our experimental setup. ❷ We developed a foot simulator.

Nursing Science for Lifestyle-Related DiseasesProfessor : Kiminori Hosoda, Kazuko Nin Associate Professor : Ikumi Honda, Hiromi Sakuda List for Tel, Fax & E-Mail : See page 000-000


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- Nursing Science - Clinical Nursing Science


You will learn nursing science for critical care and advanced medical treatment to acquire specialized knowledge and nursing skills that prepare you for sophisticated medical technologies involving considerably invasive procedures such as transplantation and heart, lung, and brain surgery, and to develop a nursing assessment capability, an ability to make clinical decisions in nursing, and practical nursing skills. From the viewpoint of holistic medicine, we guide you in utilizing knowledge based on nursing theories as well as various principles and findings in closely-related disciplines for the sake of patients and their families facing life-threatening or daily stressful situations

Research and Education In highly-advanced medicine, specifically in transplantation and regenerative medicine invasive both physically and mentally, nursing practice is essential in each of the first-aid, perioperative, critical, recovery, and self-management stages. In this course of nursing science for critical care, with a special focus on the first-aid, perioperative, critical, and recovery stages, we instruct you to explore nursing care and establish nursing models not only for patients under life-threatening conditions but for living donors (in the case of organ transplantation) and for the families concerned. The curriculum is designed in view of advanced medicine-related social policies, care systems, and ethical challenges.

Recent Publications1. Chiharu Akazawa, Ayako Okutsu, Sayoko Teraguchi et al; The Relationship Between

Postoperative Psychiatric Disorders(PPDs) and Psychosocial Factors in Adult Living-Related Liver Transplantation (LRLT) Recipients; ITNS ,2006.

2. Ayako Okutsu, Chiharu Akazawa, Sayoko Teraguchi et al; The Relationship Between Postoperative Psychiatric Disorders(PPDs) and Recovery Process of Adult Living-Related Liver Transplantation(LRLT) Recipients ; ITNS ,2006.

3. Teiko NISHIZONO, Chiharu AKAZAWA,Yuko HAYASHI, Masako MIYATA,Masae YAMAMOTO;Developing the Ability of the Self-Directed Learning through the IBL Learning Method in Adult Health Nursing Education; International Nurse Educators Conference,2007.

4. Chiharu Akazawa, Sayoko Teraguchi, Teiko Nishizono:Postoperative psychiatric symptoms(PPS) adult living-related liver transplantation(LRLT) in Japan:What are the physical and psychological factor?,JapanAcademy of Transplantation and Regeneration nursing,4(2),P1-10,2009.

5. Okamoto S, Slingsby BT, Nakayama T, Nakamura K, Fukuda R et al; Barriers to vaccination among Japanese medical students: focus group interviews. Pediatr Int. 2008; 50(3): 300-5.

❶ The Relationship Between Postoperative Psychiatric D i s o r d e r s ( P P D s ) a n d Psychosocial Factors in Adult Living-Related Liver Transp lan ta t ion (LRLT) Recipients

❷ The Relationship Between Postoperative Psychiatric D i s o r d e r s ( P P D s ) a n d R e c o v e r y P r o c e s s o f Adult Living-Related Liver Transp lan ta t ion (LRLT) Recipients

❸ Developing the Ability of the Self-Directed Learning through the IBL Learning Method in Adul t Heal th Nursing Education

Critical Care NursingAssociate Professor : Chiharu Akazawa Teaching Associate : Risa Fukuda List for Tel, Fax & E-Mail : See page 000-000

Critical Care Nursing

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There are 10 million emails sent in the world each day, 80-90% of which are said to be spam. Even in such advanced information societies, human behavior remains frivolous. This kind of human behavior cannot be unraveled with higher brain functions only. We must also consider the huge impacts on the human mind of cultures, their histories, individual life histories, and social environments. In the light of this background, psychiatric nursing will clarify the mechanisms of the mind that produce barriers in human relations, developmental problems, and the difficulty of living to achieve self-realization. Our major research theme is support that enables better mental activities and social living by means of conducting joint trials.

Shigeru SakurabaProfessor

Research and EducationWe are in charge of psychiatric nursing for mental care targeting mental problems in a wide range of human health science. In education in the graduate school we are in charge of medical psychology, psychiatric nursing theory, clinical practice and practicums. The practicums in the graduate school are essential credits to acquire a license as a clinical psychiatric nurse specialist. In addition, “Health Psychology,” which is a course common to all departments, is taught by Suga, Toichi, and Sakuraba, and the textbook has been released as a single volume in the “Kyoto University Popular Lecture Series”. In addition to the mental diseases of psychiatry, our research examines phenomena that reflect modern society such as depression, suicide, bullying, social withdrawal, and abuse. Sakuraba and Konishi use their clinical experience to conduct surveys and analysis of care of the many people with mental difficulties and ways of dealing with them, and support to help connect them to social life from the perspectives of nursing. We have conducted many studies on effective assistance methods. Suicide research in people with alcohol dependence was also conducted, part of which was picked up as news by the American Psychiatric Association. There is also a focus on psychiatric care of transplant patients in liaison psychiatric nursing, and qualitative and quantitative studies are conducted. Study results have been published by the American Society for Artificial Internal Organs. We have visited of the German Berlin Cardiac Disease Center (Deutsches Herzzentrum Berlin), and actively pursue organ transplant surveys and studies in other countries. Konishi,nursing effect caught affection change of man as the attempt to consider the effect from brain activity using brain wave or NIRS (near-infrared spectroscopy). The subjects of our studies range from toddlers to the aged of both sexes. In other words, mental problems of people from birth to death are approached from various perspectives, and mental issues in all social settings are studied. Surveys and research with research institutions in various countries are conducted on organ transplants with respect to psychiatric support and team medicine, which is essential to advanced medical care. Our aim is to train medical personnel who can aid various people mentally.

Recent Publications1. D.Milne, Sakuraba Shigeru, Matushita Masaaki. Japan Gapples with Alcoholism Crisis.

Psychiatric News (APA) 38 (23),2003. 2. Sakuraba Shigeru, Kubo Masako, Komoda Takeshi, Yamana Junichi. Suicidal Ideation and

Alexithymia in Patients with Alcoholism: A Pilot Study. Substance Use & Misuse, 40: 823-830, 2005

3. Komoda Takeshi, Drews Thorsten, Sakuraba Shigeru, Kubo Masako, Hetzer Roland. Executive Cognitive Dysfunction without Stroke after Long-Term Mechanical Circulatory Support, American Society for Artificial Internal Organs Journal, 51(6): 764-768, 2005

4. Sakuraba Shigeru, Suzuki Mayo, Tatemori Hisateru, Saito Mari, Kurita Hiroshi.Screening Scale for Pervasive Developmental Disorder : Using Tokyo Child Development Schedule and Tokyo Autistic Behavior Scales.Books of Abstracts of XIXth World Congress of World Association for Social Psychiatry:124,2007.

5. Suzuki Mayo,Sakuraba Shigeru.Coparisom of self-efficscy for social participation between competitively and non-competitively employed consumers with psychiatric disabilities.10th International Congress of Behavioral Medicine Abstract book,244,2008.

6. Suzuki Mayo, Sakuraba Shigeru. The internal world of patients with major depressive disorder. 10th International Congress of Behavioral Medicine. 2008. 8 Tokyo.

7. Sakuraba Shigeru.Eating disorders care in child and Adolescence.13th Japan Eating disorder Association,12,2009.

❶ The church of the German Berlin Cardiac Disease Center (Deutsches Herzzentrum Berlin)

❷ staffs

Psychiatric NursingProfessor : Shigeru Sakuraba Assistant Professor : Nami Konishi List for Tel, Fax & E-Mail : See page 000-000

Psychiatric Nursing

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We focus on nursing of medically dependent children and their families in terms of teaching professional knowledge and care techniques and developing nursing assessment and nursing practice abilities in order to understand the growth/development and living environments of children in the context of the falling birthrate, and help such children and their families maintain and improve their health for life. We aim to develop child/family-aiding strategies based on nursing trends in child/family-oriented theories and literature, and on the roles of child health and development nursing specialists in collaboration with related areas such as sociology, healthcare, welfare, and education.

Machiko Suzuki RN, PHN, PhDProfessor

Research and EducationFor children and their families to maintain and improve their health for life, it is important to practice nursing that targets diseases in adults, who nurture the next generation after completing their own developmental course. Thus, we provide research guidance focused on the following:

1) Development of self-help (then independence) measures for disabled children with refractory diseases, long-term hospitalized children highly dependent on medical support such as mechanical ventilation, and home-care children living in the community, as well as childrearing support for their families;2) development of network models to support abused children and families facing child abuse/death; 3) identification of ideal collaboration with various specialists in school education (for both normal and disabled children) and clarification of the professional functions and roles of nurses; and 4) development of nursing-care methods for children with cancer.

Recent Publications1. Machiko Suzuki (March 2007): Ideal support for self-help in home-care children on mechanical

ventilation -- a review of actual conditions in Chugoku and Shikoku areas and a model case in New Jersey; Child Health Research, 66(2), 315-321.

2. Machiko Suzuki (July 2006): The current status of pediatric rehabilitation in foreign countries; Pediatric Nursing, 29(8), 1137-1140.

3. Machiko Suzuki (2006): Seeking ideal home-visit nursing to support home care; Home-Visit Nursing and Nursing Care, 11(2), 139-148.

4. Machiko Suzuki (2006): Building home-care support systems for children under prolonged treatment; Nursing Education, 47(5), 389-393.

5. Machiko Suzuki (2004): A home-care support system model for children in extremely severe conditions -- 1st report: activities and results by the “review board” in the whole community; Child Health Research, 63(5), 583-589.

❶ Suzuki (the second from the right) visited a 42-year-old male patient with muscular dystrophy who had been home-cared on 24-hour mechanical ventilation for 19 years in NJ, USA, with Dr. Bach, a world authority on NIPPV, and his co-researchers to seek measures to promote self-help.

❷ Lecture meeting “Hiromi looked very pleased

with the mini-live, smiling all the time. Although I was sorry for Dr. Hatakeyama, I could not help laughing because there was a considerable difference between his lecture and attitude. His talk about ‘prior reading’ was very suggestive. With no apparent tiredness, Hiromi is now taking a lesson using the switch. We look forward to another opportunity to meet challengers and let them refresh our minds and energize us.”In a community-support event held since 2000 in Hiroshima P r e fe c t u r e fo r h o m e - c a r e children/adults highly dependent on medical suppor t such as mechanical ventilation

❸ Home-care child support system model (draft), developed based on community support activities

Development of home-care child support systems

College teaching staff-unique contribution to the community

Activities by the review board: lecture meeting, training session, exchange

meeting,case-study meeting, and direct support

Provision of oppor tunities to review and reconfirm knowledge/techniques, formation of new networks, empowerment, window ser v ice to d i rec t ly suppor t individuals.

Child Health and Development NursingProfessor : Machiko Suzuki Assistant Professor : Kanako Kiyokawa List for Tel, Fax &E-Mail : See page 000-000 URL : http://www.hs.med.kyoto-u.ac.jp/

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- Nursing Science - Family Nursing Science


The social environment within which Japanese women live has undergone remarkable change in recent years. Obstetrics in Japan is currently faced with many problems, including a falling birth rate, a shortage of obstetricians, fewer childbirth facilities, increasing numbers of infertile couples, and child abuse. These problems have arisen due to a variety of factors, including the advent of the nuclear family. The Health and Welfare Ministry has recently reinforced its strategy of support for childbearing, which aims to ensure enjoyable childbirth and childbearing in society. In this context, midwives are responsible for the care of mothers and children as their healthcare provider. As a student in this course, you will have completed advanced education with a focus on the primary healthcare needs of women throughout their entire life-cycle and will have experience as a specialist midwife and maternal and child-healthcare provider as an autonomous practitioner. Students will be expected to be able to educate midwives in theoretical knowledge and be skilled in the role of lead professional.

Kiyoko KabeyamaProfessor

Research and EducationIn the midwifery f ield, you will undertake programs specially designed to develop and achieve competencies, theory, skills, and knowledge as an autonomous practitioner attending to mothers during antenatal, intranatal, and postnatal periods and with the neonate and child. You will also ensure that students have the ability to recognize and diagnosis potential problems and complications in high-risk pregnant women and children.

In the field of women’s health, you will undertake programs concerned with the primary healthcare needs of women throughout their life-cycle, as well as how to support couples undergoing infertility treatment. This course is designed to provide students with the theoretical and practical knowledge and skills necessary to practice midwifery in a multidisciplinary context by EBN. Students will undertake independent research on a topic of interest and develop their critical, conceptual, and analytical skills, applying relevant research techniques to their chosen field of study. The program, titled “Emotional and Physical Counseling for Women,” is a collaborative venture with Kyoto University Hospital developed to promote health services and improve clinical skills.

Research topics currently covered in related family nursing include reproductive health, infertility treatment, development of perinatal management systems, women’s smoking status, and maternal nutritional management. Faculty members are currently conducting research into the promotion of health services, not only nationally but also in an international context, especially in underdeveloped countries from a global perspective.

Recent Publications1. Kabeyama K. et al. Textbook for Midwives 1~8, Igaku-Shoin, Tokyo, 2008 2. Kabeyama K. et al. Physical Examination for Midwives, Igaku-Shoin, Tokyo, 2008 3. Watanabe H. Kabeyama K. et al. A Review of Inadequate and Excessive Weight Gain in Pregnancy,

Bentham Science, 5(4), 186-192, 2009 4. Kabeyama K. Longitudinal study of the intensity of memorized labour pain, International J of

Nursing Practice, 7, 56-63, 2001 5. Chiba Y, et al. Gaps between maternity service and record-keeping in the two district hospitals in

Western Kenya. 28th Triennial Congress of International Confederation of Midwives (ICM), 2008 6. Chiba Y, Yamaguchi K, Kabeyama K. Differences between Japanese programs in acquiring

midwifery skills through practicum: Comparison of self-evaluations and instructor evaluations on student achievement. International Conference of International Confederation of Nurses (ICN), 2007

7. Gesso A. Kabeyama K. An analysis of the multipara’s concerns at the last term of pregnancy, ICN 23rd Quadrennial Congress, 302, 2005

❶ P ro f . K . Kabeyama (middle of the bottom) with staffs of Karalinska Institute, Stockholm

❷ Ultrasound scan in the midwifery diagnosis

❸ Measurement of the au tonomic ner vous functions

Midwifery & Women’s HealthProfessor : Kiyoko Kabeyama Associate Professor : Keiko Yagi Senior Lecturer : Midori Kanaoka Assistant Professor : Yoko Chiba List for Tel, Fax & E-Mail : See page 000-000

Midwifery & Women’s Health

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- Nursing Science - Family Nursing Science


Prevention is the origin of, as well as a fundamental component of community health nursing. Throughout the life cycle, from infancy to old age, preventive activities in a variety of fields of community health care are indispensable for a life of high quality. So we welcome public health nurses and health care professionals who wish to learn the methods to elucidate health promoting factors or health deteriorating factors, such as lifestyle or socio-cultural background. The program includes evidence-based preventive activities and health care, and networks and systems for preventive activities, the framing policy for the purpose of building a healthy community and promoting health of community residents.

Toshiki Katsura , R.P.H.N. , R.N. , Ph.D.Professor

Research and EducationWe aim to train public health nurses and other health care professionals in promoting independent preventive activities and research contributing to building of healthy communities. Objectives include successful aging and health promotion of community residents using epidemiological methods or other scientific methods, both quantitative and qualitative, which are currently employed in health care and health promotion activities.

Current projects include:1) Epidemiological studies in community and work populations for prevention of cardiovascular diseases or metabolic syndrome, and plan-do-see preventive approaches to lifestyle modification and weight management for overweight residents with metabolic syndrome.2) Field studies on prevention of bed-boundedness and house-boundedness aiming at successful aging in the very elderly or elderly living alone. We are involved in joint field studies and experimental studies, such as sight information processing and risk cognition in the elderly, including elucidation of mechanisms of falls and fall prevention.3) We have developed a residential space for human communications between elderly residents living alone in communities for the purpose of social experimentation on building a healthy community. This includes health promotion of community residents, and supporting resident-participant health promotion activities and framing of community networks.

Recent Publications1. Toshiki Katsura, Akiko Hoshino : Factors Relating to Maintenance of Walking to prevent against

House-boundedness in Old-old-residents. J. J. H. M.;16(1):14-24, 2007. 2. Toshiki Katsura, Kazumi Matsuda, Mari Yamazaki, Akiko Hoshino : A Follow-up Study on

Weight Management Appropriate for Improving Coronary Risk Factors – Does Moderate Middle-termed Weight Loss Improve Hypercholesterolemia ? -. J.J. H. M.;15(4):3-14, 2007.

3. Toshiki Katsura, Kazumi Matsuda, Mari Yamazaki, Akiko Hoshino. Prevalence of Metabolic Syndrome in 400,000 Japanese Employees Resided in All Prefectures, Japan; J.H.M.A. : 14(4), 2-6, 2006.

4. Akiko Hoshino, Toshiki Katsura, Masae Yamamoto : Examination of a Satellite System at a Local Shopping Center for Supporting Independent Living of Elderly People – SUKOYAKA Salon -. J. J. R. M.;55(4):402-407, 2006.

5. Toshiki Katsura, Akiko Hoshino : Characteristics of Independent Moving Ability in Elderly Residents – Comparison of Physical Factors Relating to Walking Ability between young-old and old-old-residents-. J. J. H. M.;14(4):16-23, 2006.

6. Akiko Hoshino, Toshiki Katsura : Effects of Activities of Community Organization in a Local city –Comparison of Health Behaviors of Continuators and Those of Retirees of Hoken-suisinin Activities in F-city -.J. J. H. M.;14(2):33-36, 2005.

❶ Characteristics in the fixation point and the visual search of an elderly faller in comparison with an elderly or a middle aged non-faller during descending stairs of a pedestrian bridge

(T Katsura, N Miura, N Takahashi, S Hisamoto and A Hoshino ) ❷ BMI curve in males (above) and females (below) of 400,000 Japanese aged 25-75 ( T Katsura, K Matsuda, M Yamazaki and A Hoshino ) ❸ “Sukoyaka” health lectures aiming at successful aging are held to promote health of

community residents about 6 times for a year in Kyoto

Preventive NursingProfessor : Toshiki Katsura , R.P.H.N. , R.N. , Ph.D. Senior Lecturer : Mika Okura Assistant Professor : Kanae Usui , R.P.H.N. , R.N. , M.N.S. List for Tel, Fax & E-Mail : See page 000-000

Preventive Nursing

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- Nursing Science - Community Health and Community Health Nursing


As the population ages, the need to fully understand the pathogenesis of dementia and to develop its effective method for care is vital to our nation. Therefore, the mission of our section is to help the person with the disease, and caregivers, family members to empower the abilities that remain. Within this mission, one objective is to foster new lines by bringing together basic and clinical science with an emphasis on Alzheimer’s disease and related disorders. We welcome the young scientists who have interests in dementia research.

Ayae Kinoshita, MD, PhDProfessor

Research and Education1)Pathogenesis of Alzheimer’s diseaseThe exact nature of neuronal dysfunction in Alzheimer’s disease remains largely unknown. For the last 10 years, we have focused on the protein Presenilin 1 (PS1), a causative protein for familial Alzheimer’s disease in order to reveal its pathogenesis. We are now currently pursuing the mechanisms which influence the PS1 localization and functions. We identified several factors to regulate PS1 function and are now currently analyzing them in vitro and in vivo. 2)Development of internet-based telenursingIn order to support the homecare for the dementia patients, there is a need for the bi-directional, communicative and economical approach between the patients and the medical staff. We develop and provide a new strategy to help the dementia patients and caregivers by internet-based webcamera.

Recent Publications1. 木下彩栄　老年性認知症「ガイドライン　外来診療 2009」日経メディカル　p395-402 2. Uemura K, Lill CM, Banks M, Asada M, Aoyagi N, Ando K, Kubota M, Kihara T, Nishimoto T,

Sugimoto H, Takahashi R, Hyman BT, Shimohama S, Berezovska O, Kinoshita A. N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio.J Neurochem. 2009, 108:350-60

3. スカイプとWebカメラを使用した在宅認知症患者とその介護者への支援：保利美也子、久保田正和、木下彩栄　癌と化学療法、35 (1) 46-47. 2008

4. 植村健吾、安藤功一、久保田正和、木下彩栄：gammaセクレターゼとシナプス機能　Cognition & Dementia 7, 46-54 (2008).

5. Uemura, K., Kuzuya, A., Shimozono, Y., Aoyagi., N., Ando, K., Shimohama, S., & Kinoshita, A. GSK3beta activity modifies the localization and function of presenilin1. J Biol.Chem. 282, 15823-32 (2007).

6. Uemura K., Kuzuya, A., Aoyagi, N., Ando, K., Shimozono, Y., Ninomiya, H., Shimohama, S., Kinoshita, A. Amyloid beta inhibits ectodomain shedding of N-cadherin via down-regulation of cell-surface NMDA receptor. Neuroscience 145:5-10 (2007)

7. Uemura, K., Kihara T., Kuzuya, A., Okawa, K., Bito H, Ninomiya H, Sugimoto H, Shimohama S., and Kinoshita, A: Modulation of beta-catenin nuclear signaling via epsilon-cleavage of N-cadherin. Biochem Biophys Res Commun 345:951-8 (2006)

8. Uemura, K., Kihara T, Kuzuya, A., Okawa, K., Sugimoto H, Shimohama S., and Kinoshita, A: Characterization of N-cadherin cleavage by ADAM10 and Presenilin 1. Neurosci Lett.402:278-13 (2006)

❶ The research o f the N-cadher in cleavage by Presenilin 1. The PS1-m e d i a t e d N - c a d h e r i n c l e ava g e releases its cytoplasmic domain from the membrane and transactivate beta-catenin. PS1 is considered to have an important effect on regulating signal transduction.

❷ Our hypothesis of Alzheimer’s disease pathogenesis. PS1 dysfunction may be causally linked to synaptic failures and other neuronal damages. We consider PS1 as a molecular switch to regulate various signaling cascades by cleaving membranous proteins.

❸ An example of a new IT-based support system for the dementia patients and caregivers.

Home Healthcare NursingProfessor : Ayae Kinoshita Assistant Professor : Masakazu Kubota List for Tel, Fax & E-Mail : See page 000-000

Home Healthcare Nursing

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- Nursing Science - Community Health and Community Health Nursing


A human body consists of a number of cells called 60 trillion. These cells interact each other and response for environmental signal to form a precise human body system. We are trying to understand various biological phenomena involving this system with a molecular level, especially by focusing on carbohydrates expressed on proteins. Moreover, we hope that the result of our research can contribute to develop a diagnosis at super-early stage of disease. We would like to advance research with young students having a dream.

Shogo Oka, Kuniaki SaitoProfessor

Research and EducationDecoding of the biological information in sugar chains (Oka): The function of proteins is regulated in vivo not only by transcriptional control of gene expression but also by post-translational modifications. Glycosylation is one of the major post-translational modifications and a large number of proteins, in fact, undergo this modification. In the post-genomic era, it is very important to decode the biological information encoded in the sugar chains. In our project we focus on structure and function of sugar chains expressed in the nervous system and in development during embryogenesis. To elucidate the roles of the HNK-1 carbohydrate expressed in the nervous system, we have succeeded in generating GlcAT-P gene-deficient mice. The GlcAT-P -/- mice exhibited reduced long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses and defects in spatial memory formation.

The physiological significance of IDO in CNS disorders (Saito): Indoleamine-2,3-dioxygenase(IDO) production by macrophages and dendritic cells has recently been demonstrated to result in the inhibition of T cell proliferation due to tryptophan depletion by this enzyme. A schematic diagram illustrating the possible role of IDO induction in inflammatory CNS disorders is shown in the figure. IDO plays an important physiological role (both beneficial and detrimental) in the CNS. It has become clear that IDO expression in the CNS is more complicated, to be sure, but regulation of IDO induction must be an ideal therapeutic target to modulate symptoms of various CNS disorders.Study on acute inflammation associated with transplant rejection (Ikemoto): f fWe found a protein that remarkably increased in the serum of the recipients with transplant rejection. This protein is produced by macrophage and/or activated neutrophils in an early stage of acute inflammation, although its functional role remains unclear. We recently found that the protein could indirectly regulate excessive inflammatory responses by binding with inflammatory cytokines nonspecifically. Our goal is to resolve expression mechanism and functional role of the protein in these immunological cells.

Recent Publications1. Tagawa, H. et al. (2005) Non-sulfated form of the HNK-1 carbohydrate is expressed in mouse

kidney. J. Biol. Chem. 280, 23876-23883. 2. Fujigaki H, Saito K (2006) Nitration and inactivation of indoleamine-2,3-dioxygenase by

peroxynitrite.J Immunol. 176:372-379. 3. Shiba, T. et al. (2006) Crystal structure of GlcAT-S, a human glucuronyltransferase, involved in the

biosynthesis of the HNK-1 carbohydrate epitope. Proteins 65, 499-508. 4. Kizuka, Y. et al. (2006) Physical and functional association of glucuronyltransferases and

sulfotransferase involved in HNK-1 biosynthesis. J. Biol. Chem. 281, 13644-13651. 5. Ikemoto, M. et al. (2007) Intrinsic function of S100A8/A9 complex as an anti-inflammatory

protein in liver injury induced by lipopolysaccharide in rats. Clin. Chim. Acta. 376, 197-204.

Basic Laboratory ScienceProfessor : Shogo Oka, Kuniaki Saito Associate Professor : Masaki Ikemoto Assistant Professor : Yasuko Yamamoto List for Tel, Fax & E-Mail : See page 000-000

Basic Laboratory Science

- Laboratory Science - Medical Laboratory Science


The cause of diseases can be largely classified into tumor, infection, heredity, hemodynamic disorder, immune disorder, metabolic disorder, and environmental factor, while we focus our researches on tumor, heredity, and infection. Our objective is to study the nature of diseases regardless of the field of laboratory testing, and we believe the outcome will help the development of laboratory testing studies. We educate students about these causes of diseases through lectures and experiments. We coordinate with the department of clinical laboratory and the department of diagnostic pathology so that we can integrate basic and clinical medicine.

Tetsuya TakakuwaProfessor

Research and Education1. Analysis of spontaneous B-cell lymphoma forming mice (collaboration with Forensic Medicine and Molecular Pathology, Graduate School of Medicine) (Takakuwa)To identify genes responsible for lymphoma formation, by analyzing SL/Kh mice which spontaneously form pre B-cell lymphoma more than 90% by six months old.2. Analysis of the pathology and the developmental mechanism in inborn errors (collaboration with Congenital Anomaly Research Center, Graduate School of Medicine) (Takakuwa)Congenital Anomaly Research Center stores several ten thousands of human embryo samples. To explore normal human development and find novel abnormalities and diseases, and the cause of them, by utilizing non-invasive, 3-dimensional analysis method like MR imaging and EFIC imaging.3. Application of novel 3-dimensional morphological analysis method to pathological diagnosis (collaboration with Congenital Anomaly Research Center, Graduate School of Medicine) (Takakuwa)To apply non-invasive, 3-dimensional analysis method like MR imaging and EFIC imaging to pathological diagnosis.4. Mechanism of humoral immune response against retrovirus infection (Ibuki)We are trying to develop an extremely sensitive ELISA for measurement of an anti-virus specific antibody against SIV or SHIV and with it, examine whether humoral immunity is related to control of the virus multiplication in the monkeys infected with SIV or SHIV.5. Study on the mechanism of resistance against anti-HIV-1 drugs using SHIV-monkey model. (collaboration with Lab. for Viral Replication, I.V.R.) (Ibuki)To elucidate the acquisition mechanism of drug-resistance of HIV-1 during ART (anti-retroviral therapy), we analyze the viral mutation in rhesus macaques infected with SHIV having the HIV-1 pol gene before and after ART.

Recent Publications1. Richard H. Kaszynski Takakuwa T et al, A quantitative trait locus responsible for inducing B-cell

lymphoblastic lymphoma is a hotspot for microsatellite instability, Cancer Sci, in press 2. Oji Y, Takakuwa T, et al, WT1 IgG antibody for early detection of nonsmall cell lung cancer and

as its prognostic factor. Int J Cancer. 2009;125(2):381-7. 2. 3. Takakuwa T, et al, Aberrant somatic hypermutations in thyroid lymphomas, Leukemia

Research2009 ;33(5):649-54. 4. Nur Rahadiani; Takakuwa T, et al, Latent membrane protein 1 of Epstein-Barr virus induces the

expression of B-cell integration cluster, a precursor form of microRNA-155, in B lymphoma cell lines, BBRC, 2008;377(2):579-83.

5. Fukazawa Y, Miyake A, Ibuki K, Inaba K, Saito N, Motohara M, Horiuchi R, Himeno A, Matsuda K, Matsuyama M, Takahashi H, Hayami M, Igarashi T, Miura T.: Small intestine CD4+ T cells are profoundly depleted during acute simian-human immunodeficiency virus infection, regardless of viral pathogenicity. J Virol. 2008 82(12):6039-44.

6. Liu A, Takakuwa T, Fujita S, Luo WJ, Tresnasari K, van den Berg A, Poppema S, Aozasa K: ATRalterations in Hodgkin's lymphoma. Oncology Report 19(4):999-1005, 2008.

7. Takakuwa T, Tresnasari K, Rahadiani N, Miwa H, Daibata M, Aozasa K, Cell origin of pyothorax-associated lymphoma; a lymphoma strongly associated with Epstein-Barr virus infection, Leukemia, 22(3):620-7, 2008.

❶ Stage 56 Embryo MR imaging. ❷ Virus particle and genome structure

of SHIV.

Innovational Laboratory MedicineProfessor : Tetsuya Takakuwa Associate Professor : Kentaro Ibuki List for Tel, Fax & E-Mail : See page 000-000

Innovational Laboratory Medicine

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- Laboratory Science - Medical Labolatory Science


Laboratory science aims to establish and realize concepts and methods for extracting and analyzing various information from molecular and cellular levels to the organ level, for the purpose of elucidating structure and function of livings, clarifying etiology and pathophysiology of various diseases and establishing diagnosis and treatment of diseases. In this area, we focus on structural and functional analysis indispensable for diagnosis of treatment of diseases. Accordingly, we promote studies on new concept and technology on the basis of medicine, biology and information technology. We intend to encourage new talents who will act as a leader in the fields of education, research and clinical practice.

Souichi Adachi, Akihiko Nakaizumi, Masatoshi FujitaProfessor

Research and Education【Adachi Labo】Many hematologic malignancies of children have been cured because of progression of treatments. But, still some of these patients relapse or suffer serious complications. Our laboratory has many projects related with new treatments or diagnostic tools in these patients. (1) Mechanism of new type of cell death induced by molecular target therapy (2) Development of new treatments and new prognostic factors in child AML (3) Analysis of serious complications in patients after stem cell transplantation.【Nakaizumi Labo】Our aim is to bring up a talented person familiar with various laboratory examinations related to pancreatobiliary malignancies. I hope that he/she will play an active role as an equal partner of gastroenterologist in the clinical setting.Our laboratory has many projects related with new diagnostic tools or treatments in the patients with pancreatobiliary malignancies.(1) Early diagnosis of pancreatobiliary malignancies (2) Endoscopic diagnosis and treatments (3) Analysis of the high risk group for pancreatic cancer and development of the medical checkup system for the early detection of pancreatic cancer (4) Conventional or rapid cytological examinations in digestive malignancies.【Fujita Labo】Our aim is to bring up a talented person familiar with various laboratory examinations related to cardiovascular disease. I hope that he/she will play an active role as an equal partner of cardiologist in the clinical setting.1)Development of acceleration bed for improving QOL of elderly2)Significance of smoking as a deteriorating factor of chronic fatigue syndrome3)Development of molecular targeting treatment for heart failure with administration of curcumin

Recent Publications1. Watanabe M, Adachi S, Matsubara H, Imai T, Yui Y, Mizushima Y, Hiraumi Y, Watanabe K,

Kamitsuji Y, Toyokuni S, Hosoi H, Sugimoto T, Toguchida J, Nakahata T: Induction of autophagy in malignant rhabdoid tumor cells by the histone deacetylase inhibitor FK228 through AIF translocation. Int J Cancer 124:55-67, 2009

2. Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y, Watanabe M, Matsubara H, Mizushima Y, Hiraumi Y, Kawata E, Yoshikawa T, Maekawa T, Nakahata T, Adachi S: The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ 15:1712-1722, 2008

3. H Uehara, A Nakaizumi, O Ishikawa, H Iishi, K Tatsumi, R Takakura, T Ishida, Y Takano, S Tanaka, A Takenaka. Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas. Gut 2008 Nov; 57: 1561-5

4. H Uehara, K Tatsumi, E Masuda, M Kato, T Kizu, T Ishida, R Takakura, Y Takano, A Nakaizumi, O Ishikawa, A Takenaka. Scraping cytology with a guidewire for pancreatic-ductal strictures. Gastrointest Endosc. 2009 Feb; 25

5. Fukuda S, Shimada K, Kawasaki T, Kono Y, Jissho S, Taguchi H, Maeda K, Yoshiyama M, Fujita M, Yoshikawa J: “Passive exercise” using whole body periodic acceleration: effects on coronary microcirculation. American Heart Journal 159(4):620-626, 2010.

6. Miyamoto S, Fujita M, Inoko M, Oba M, Hosokawa R, Haruna T, Izumi T, Saji Y, Nakane E, Abe T, Ueyama K, Nohara R: Effect on treadmill exercise capacity, myocardial ischemia, and left ventricular function as a result of repeated whole-body periodic acceleration with heparin pretreatment in patients with angina pectoris and mild left ventricular dysfunction. The American Journal of Cardiology 107(2):168-174, 2011.

7. Miwa K, Fujita M: Fluctuation of serum vitamin E (α-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome. Heart and Vessels 25(4):319-323, 2010.

8. Ohigashi H, Ishikawa O, Eguchi H, Takahashi H, Gotoh K, Yamada T, Yano M, Nakaizumi A, Uehara H, Tomita Y, Nishiyama K: Feasibility and efficacy of combination therapy with preoperative full-dose gemcitabine, concurrent three-dimensional conformal radiation, surgery, and postoperative liver perfusion chemotherapy for T3-pancreatic cancer. Ann Surg. 250:88-95.2009

❶ Adachi's Lab ❷ Fujita's Lab ❸ Nakaizumi's Lab

Applied Laboratory ScienceProfessor : Souichi Adachi, Akihiko Nakaizumi, Masatoshi Fujita Assistant Professor : Hiroshi Itoh List for Tel, Fax& E-Mail : See page 000-000

Applied Laboratory Science

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- Laboratory Science - Medical Laboratory Science


[Akitoshi Seiyama (Professor)] We are developing new technologies to visualize biophysical and physiological functions inside the living body, especially to visualize human brain function. Further, we aim to reveal mechanisms of such individual bio-phenomena through animal experiments.[Satoshi Sasayama (Associate Professor)] We are conducting various data analysis and information system development by utilizing statistics and ergonomics. Specifically, we are constructing a pathogenic bacteria database, an e-Learning system, and some interactive learning materials in the fields of health science. Akitoshi Seiyama

Professor

Research and Education[Akitoshi Seiyama (Professor)]We are developing new technologies to visualize biophysical and physiological functions inside the living body. In vivo molecular imaging, an important technique in the post-genome strategy, has the potential to visualize the dynamics of individual bio-phenomena processes in cells, organs as well as in the living body. We aim to reveal mechanisms of such individual bio-phenomena in the living body through bio-imaging using MRI, Near-IR optical imaging and electrophysiological techniques.[Satoshi Sasayama (Associate Professor)] We are construct ing a pathogenic bacter ia database (PBDB) to provide the basic knowledge on bacteriology not only to the researchers and specialists on microbiology but also to students and general public through the Internet. This system serves picture information, such as high-quality images of bacteria and of analysis materials, moving images with narration of assay procedures, and so on. We are also constructing an e-Learning system, and some interactive learning materials intended for students and alumni of health science.

Recent Publications1. Jin T, Fujii F, Komai Y, Seki J, Seiyama A, Yoshioka Y: Preparation and Characterization of Highly

Fluorescent, Glutathione-coated Near Infrared Quantum Dots for In Vivo Fluorescence Imaging. Int J Mol Sci 9(10):2044-2061, 2008

2. Jin T, Yoshioka Y, Komai Y, Seki J, Seiyama A: Gd3+-Functionalized Near-Infrared Quantum Dots for In Vivo Dual-modal (Fluorescence/Magnetic Resonance) Imaging. Chem Commun (Camb) 30(44): 5764-5766, 2008

3. Seiyama A: Dissociation of Stimulus-Induced Responses in Regional Cerebral Blood Flow and Blood Volume in the Visual Cortex of Humans. 健康科学 4: 7-18,2007

4. Kohno S, Miyai I, Seiyama A, Oda I, Ishikawa A, Tsuneishi S, Amita T, Shimizu K: Removal of the skin blood flow artifact in functional near-infrared spectroscopicimaging data through independent component analysis. J Biomed Opt 12: 062111(1-9), 2007

5. Li JY, Ueda H, Seiyama A, Seki J, Konaka K, Yanagida T, Sakoda S, Yanagihara T: Ischemic vasoconstriction and tissue energy metabolism during global cerebral ischemia in Gerbils. J Neurotrauma 24: 547-558,2007

Medical Devices for DiagnosesProfessor : Akitoshi Seiyama Associate Professor : Satoshi Sasayama List for Tel, Fax & E-Mail : See page 000-000

Medical Devices for Diagnoses

- Laboratory Science - Information Technology and Medical Engineering


Among biomedical imaging technologies, image information processing applicable to computer assisted diagnosis and ultra high resolution MRI are focused in this group. Medical image data obtained from such as CT and MRI becomes larger so as to provide medical staff with higher quality images. One of our objectives is to develop image information processing algorithm and systems to assist doctors in extracting necessary information from the huge data by more precise and more effective way. In order to obtain molecular/cell level information, we are also developing the ultra high resolution MRI equipment.

Naozo Sugimoto, PhD (in Eng.)Professor

Research and Education* Biomedical imaging devicesWe have been developing an ultra high resolution Magne t i c Resonance Imaging (MRI) as a microscopy, "MRI Microscopy". Among imaging technologies, MRI is in an unique position due to its abilities to localize activating parts in biomedical specimen and to distinguish tissue non-invasively. With the MRI Microscopy, we could understand human brain functional images from the molecular and cell biological point of view. We started to develop a new MRI Microscope for small biological tissue using a 14.1 T horizontal bore magnet and a 600 MHz NMR spectrometer.

* Image processing methods and its medical applicationsWe develop image processing techniques for quanti tat ive analysis of mult i dimensional medical images including multi modality images or sequential images. We also develop medical applications such as image guided radiotherapy, image guided intervention, CAD(computer aided diagnosis) system, and so on. An example of the work is shown in the right column figure (4-dimensional cardiac MR tagged imaging and 5-dimensional image processing methods).

Recent Publications1. S. Urayama, N. Sugimoto, et al., Four-dimensional MR tagged imaging and image processing.

International Journal of Computer Assisted Radiology and Surgery, Vol. 1-Suppl., pp.107-109(2006)

2. H. Sekiguchi, N. Sugimoto, et al., An image processing on regular coronary angiograms for myocardial perfusion measurement. Computers in Cardiology, Vol.33, pp.821-824(2006)

3. F. Voci, S. Eiho, N. Sugimoto, and H. Sekiguchi, Estimating the gradient threshold in the Perona-Mlik equation. IEEE Signal Processing Magazine, Vol.21, No.3, pp. 39-46(2004)

4. T. Ueno, S. Balibar, T. Mizusaki, F. Caupin, E. Rolley, Critical Casimir effect and wetting by helium mixtures. Physical Review Letter 2003;90:116102.

5. T. Ueno, M. Fujisawa, K. Fukuda, Y. Sasaki, and T. Mizusaki, Visualization of phase-separated boundary in liquid 3He-4He mixtures by MRI, Physica B 284-288, 2057-2058 (2000).

❶ Four-dimensional cardiac MR tagged imaging and image processing.

❷ Previously developed MR microscope with 7-T magnet.

❸ Staff with 14-T MR magnet for a new MR microscope.

Innovative Medical Imaging TechnologyProfessor : Naozo Sugimoto, Ph.D. Assistant Professor : Tomohiro Ueno, Ph.D. Program-Specific Assistant Professor : Koji Sakai, Ph.D. List for Tel, Fax &E-Mail : See page 000-000


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- Information Technology and Medical Engineering


Aiming to earlier diagnosis, improved accuracy of diagnosis and adequate treatment support, in our laboratory, we have researched advanced medical equipment. The topics being studied cover both of the fundamental research and clinical application. The former includes developing real-time and non-invasive sensing and imaging of biomedical information, which is relevant to tissue characteristics and function in addition to morphology. The latter includes applications of advanced ultrasound and optical imaging technology to diagnosis and minimally-invasive treatment support of diseases such as beast cancer, chronic hepatitis, myocardial infarction.

Tsuyoshi Shiina, PhD (in Eng. & Med. Sci) Professor

Research and EducationNowadays, non-invasive imaging equipment such as CT, MRI, US is indispensable to medical care. However, diagnostic information about tissue characteristics and function is insufficient compared with morphological information. Then, there is a real need for development of advanced medical imaging modalities for earlier diagnosis and more accurate differential diagnosis. In our laboratory, using ultrasound which has the advantage of being non-invasive, real-time, many biomedical imaging technologies such as 3-D blood flow vector imaging, myocardial contractility imaging have been investigated. As for imaging of tissue characteristics, real-time tissue elasticity imaging has been developed in our laboratory and world’s first practical use of elasography for breast cancer diagnosis was achieved in collaboration with industries and university.In recent years, we started research on novel non-invasive imaging modality which combines ultrasound and optics, in the project ‘Innovative Techno-Hub for Integrated Medical Bio-imaging’ financed by JST and MEXT. Including this, we are now working the following research topics.(1)Ultrasound tissue elasticity imaging a)Breast cancer, prostate cancer diagnosis b)Quantitative assessment of arteriosclerosis c)Staging of fibrosis and CAD for hepatic cirrhosis (2)Myocardial contractility imaging (3)3-D blood flow imaging(4)Fusion technology of ultrasound and optical imaging (5)Ubiquitous medical image diagnosis (6)Theory for non-invasive biomedical measurement and medical imaging analysis.Through these research works, we also aim to foster human resource to be active in wide fields from development of medical equipment to clinical practice.

Recent Publications1. H. Nakagawa, S. Ueno, T. Shiina, M. Kotani, S. Kubota, "Application of radical chain reactions

to drug release controlling of liposomal carriers under high magnetic fields," Journal of Applied Physics, Vol. 105, 07B323, 2009.

2. T. Shiina, M. Yoshida, M. Yamakawa, N. Nitta: “Microscopic Measurement of Three-Dimensional Distribution of Tissue Viscoelasticity,” Acoustical Imaging, pp.11-18, 2008.

3. T. Shiina: “In vitro 3-D Measurement of Tissue Viscoelasticity by Ultrasound”, Int. Journal of Appl. Biomed. Eng. Vol.1, No.1, pp.1-6,2008.

4. H. Nakagawa, T. Shiina, M. Sekino, M. Kotani, S. Ueno: “Fusion and Molecular Aspects of Liposomal Nanocarriers Incorporated with Isoprenoids,” IEEE Trans. NanoBioscience, Vol. 6, pp. 219-222, 2007.

5. A. Itoh, E. Ueno, E. Tohno, H. Kamma, H. Takahashi, T. Shiina, M. Yamakawa, T. Matsumura: “Breast Disease: Clinical Application of Ultrasound Elastography for Diagnosis,” Radiology, Vol. 231, No. 2, pp. 341-350, 2006.

❶ Ultrasound t issue elastici ty imaging equipment(elasography)

❷ Elastogram of breast cancer(non-invasive ductal carcinoma )

❸ Assessment of coronary plaque using IVUS elastography

❹ Ubiquitous medical image diagnosis

Medical Imaging System SciencesProfessor : Tsuyoshi Shiina Associate Professor : Kenichi Otsuka Program-Specific Assistant Professor : Shuhui Bu List for Tel, Fax & E-Mail : See page 000-000


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- Laboratory Science - Information Technology and Medical Engineering


Our laboratory has made a significant progress in research of motor function using morphological, biochemical, physiological and biomechanical methodology. From the standpoint of rehabilitation, nervous system, skeletal muscles and articular cartilage are especially studied in our laboratory and a novel walking assist system is also studied in the clinical field of elderly persons and patients with osteoarthritis. In the near future, research in community and sports fields will be started. The aim of our laboratory is to bring up talented young scientists who can promote studies in prevention for disease and who can contribute to rehabilitation for minimizing functional disabilities based on elucidation of mechanisms of disease and disabilities.

Hiroshi Kuroki, Makoto IshibashiProfessor

Research and EducationRecent studies in our laboratory have revealed novel evidences on properties of ultrasound echo from articularcati lage, roles of Sonic hedgehog (Shh) signaling,and properties of the skeletal muscle of cerebral palsy. Based on these achievements, we are currently pursuing the following research projects.1) Because articular cartilage has limited healing capacity, the cartilage of osteoarthritis rarely repair spontaneously. Raw wave of ultrasound echo from articular cartilage and its wavelet transform reveals features of acoustic properties in such osteoarthritic cartilage and postoperative cartilage (Figure 1). Our ultrasound assessment for articular cartilage is one of the advanced research projects in the world. Relationship between ultrasound echo and collagen is also studied. Based on these evidences, rehabilitation for human knee cartilage and prevention of functional disability of knees are promoted in our clinical field.2) A novel walking-assist system is studied. In this system the elderly persons and patients with osteoarthritis can walk with low energy and without joint pain because their body weight can be reduced to 25 % using positive air pressure (Figure 2). 3) In order to understand how the head region and the central nervous system are patterned during embryogenesis, specifically, we analyze the knock-out mice to examine roles of Sonic hedgehog (Shh) signaling in formation of the brain (Figure 3). FGF signaling is also being analyzed to elucidate the mechanisms of how the head region is determined. In addition, mathematical models are hypothesized and tested by experiments to clarify the behaviors of signaling molecules.4)Walking training for the patients with central nervous system disorders and muscle strengthening for the children with central nervous system disorders are studied.5) Psychological process in palliative medicine and terminal care for the cancer patients is studied.6) Rehabilitation approach and assessment for the elderly people is studied. In pursuing these research projects, we focus on training of scientists in a wide variety of techniques in ultrasound measurement of articular cartilage, histopathology of degenerated cartilage, chondrocyte culture, and gait rehabilitation as well as up-to-date knowledge in the related fields. We welcome young students to our laboratory and hope them working together to create new aspects in rehabilitation research.

Recent Publications1. Ohata K, Tsuboyama T, Haruta T, Ichihashi N, Nakamura T. Longitudinal change in muscle and fat

thickness in children and adolescents with cerebral palsy. Dev Med Child Neurol. 2009; May 11. [Epub ahead of print]

2. Kuroki H, Nakagawa Y, Mori K, Kobayashi M, Yasura K, Okamoto Y, Suzuki T, Nishitani K, Nakamura T. Ultrasound has the potential to detect degeneration of articular cartilage clinically, even if the information is obtained from an indirect measurement of intrinsic physical characteristics. Arthritis Res Ther. 2009;11(3):408.

3. Kuroki H, Nakagawa Y, Mori K, Kobayashi M, Nakamura S, Nishitani K, Shirai T, Nakamura T. Ultrasound properties of articular cartilage immediately after osteochondral grafting surgery: in cases of traumatic cartilage lesions and osteonecrosis. Knee Surg Sports Traumatol Arthrosc. 2009;17(1):11-8.

4. Maeda Y, Kobori E, Kubota Y, Seki S, Takada K, Kuramoto N, Hiraide A, Morimoto T. Major qualitative research methods in patient-doctor communication studies. Gen Med 2008;9(1):5-12.

5. Komada M, Saitsu H, Kinboshi M, Miura T, Shiota K, Ishibashi M. Hedgehog signaling is involved in development of the neocortex. Development. 2008;135(16):2717-27.

6. Miura T, Hartmann D, Kinboshi M, Komada M, Ishibashi M, Shiota K: The cyst-branch difference in developing chick lung results from a different morphogen diffusion coefficient. Mech Dev. 2009;126:160-172.

7. Kuroki H, Nakagawa Y, Mori K, Kobayashi M, Yasura K, Okamoto Y, Suzuki T, Nishitani K, Nakamura T. Ultrasound properties of articular cartilage in the tibio-femoral joint in knee osteoarthritis: relation to clinical assessment (International Cartilage Repair Society grade). Arthritis Res Ther. 2008;10(4):R78.

8. Komada M, Saitsu H, Shiota K, Ishibashi M. Expression of Fgf15 is regulated by both activator and repressor forms of Gli2 in vitro. Biochem Biophys Res Commun. 2008;369(2):350-6.

9. Ohata K, Tsuboyama T, Haruta T, Ichihashi N, Kato T, Nakamura T. Relation between muscle thickness, spasticity, and activity limitations in children and adolescents with cerebral palsy. Dev Med Child Neurol. 2008;50(2):152-6.

❶ Raw waves of echo from articular cartilage (bottom) and wavelet transform (top) ❷ A novel walking assist system using positive air pressure ❸ Expression of Sonic hedgehog (Shh) in chick embryo (in situ hybridization)

Motor Function AnalysisProfessor : Hiroshi Kuroki, Makoto Ishibashi Senior Lecturer : Koji Ohata Yuko Maeda Assistant Professor : Tome Ikezoe List for Tel, Fax & E-Mail : See page 000-000

Motor Function Analysis

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- Rehabilitation Sciences - Physical Therapy, Rehabilitation Sciences


Rehabilitation is the process of developing oneself again so that one can show the highest ability in daily living. Rehabilitation creates a new life. Importance is being added to rehabilitation with the increasing application of advanced medical treatment and change in the structure of society. We try to promote research on the mechanisms of motor dysfunction, the development of new function, and compensatory methods assisted by up-to-date technology. With these approaches, we are aiming at the establishment of advanced rehabilitation systems.

TadaoTsuboyama, Noriaki Ichihashi, Professor

Research and EducationWe intend to produce excellent rehabilitation professionals who, with broad horizons, can cope with many problems in both clinical and social settings. We proceed with research in cooperation with Kyoto University Hospital on the theoretical aspects of motor disability and practical reconstructive strategies. Specific themes are as follows:

1.Analyses of functional disorders caused by musculoskeletal diseases.

2.Clinical and biomechanical investigations on the physiotherapy of the locomotor system.

3.Evaluation systems for physiotherapy.

4.Investigation on stretching

5.Investigation on training effectiveness

6.Analyses of the factor of falling in elderly people.

7.Investigation to prevent falling; exercise training.

Recent Publications1. Tateuchi H, Tsukagoshi R, Fukumoto Y, Oda S, Ichihashi N.: Dynamic hip joint stiffness in

individuals with total hip arthroplasty: Relationships between hip impairments and dynamics of the other joints. Clinical Biomechanics. 2011(in press)

2. Ikezoe T, Mori N, Nakamura M, Ichihashi N. : Atrophy of the lower limbs in elderly women: is it related to walking ability? European journal of applied physiology. 2011 (in press)

3. Nagai K, Inoue T, Yamada Y, Tateuchi H, Ikezoe T, Ichihashi N, Tsuboyama T. : Effects of toe and ankle training in older people: A cross-over study. Geriatr Gerontol Int. 2011(in press)

4. Ohata K, Yasui T, Tsuboyama T, Ichihashi N. : Effects of an ankle-foot orthosis with oil damper on muscle activity in adults after stroke. Gait Posture. 2011 Jan;33(1):102-7.

5. Yamada M, Tanaka B, Nagai K, Aoyama T, Ichihashi N. : Trail-walking exercise and fall risk factors in community-dwelling older adults: preliminary results of a randomized controlled trial. J Am Geriatr Soc. 2010 Oct;58(10):1946-51.

❶ Analyses of biomechanics; 3-dimentional optical operating analysis, ground reactive force monitor, electro-myogram

❷ Ultrasound image ❸ 3-dimensional gait analysis using treadmill without loading pressure ❹ Sitting pressure

Development and Rehabilitation of Motor FunctionProfessor : Noriaki Ichihashi, TadaoTsuboyama Associate Professor : Tomoki Aoyama Assistant Professor : Hiroshige Tateuchi, Minoru Yamada List for Tel, Fax & E-Mail : See page 000-000

Development and Rehabilitation of Motor Function

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- Rehabilitation Sciences - Physical Therapy, Rehabilitation Sciences


The rehabilitation has become very important in countries facing severe population aging. We aim at improving quality of life of clients with physical, psychological, cognitive or developmental limitations and are studying functional recovery for improved quality of life using various techniques in neuroscience, such as brain imaging techniques. Such an approach requires us to join multidisciplinary forces including occupational and physical therapies. We welcome young enthusiastic students interested in rehabilitation sciences regardless of their educational backgrounds.

Motomi Toichi, Toshiko Futaki, Akira MitaniProfessor

Research and EducationOur group consists of three laboratories.In Aging, Environment and QOL research lab, we focus on exploring issues related to older adults' cognitive functioning and activity in every day living in a variety of environments including community, long-term and institutional living situations from the perspective of consumers, family members and health care providers. We have also explored issues in aging with an intellectual disability and adaptation from cognitive neuroscientific perspectives (Fig. 1).In Cognitive Neurophysiology lab, we aim at the clarification of neural and cognitive mechanisms that underlie clinical and behavioral problems associated with psychiatric and developmental disorders, which include schizophrenia, mood disorder, autistic disorder, Asperger’s disorder and AD/HD. Our main research technique consists of electroencephalography, event-related potentials, near-infrared spectroscopy, functional MRI as well as cognitive psychological measurements. We try to incorporate our findings into the therapeutic practice in order to establish more effective and evidence-based intervention (Figs. 2, 3).In Neuroscience lab, we focus on a neural mechanism of functional recovery providing a neural substrate to underpin rehabilitation and try to develop novel rehabilitation strategies (neuroscience-based rehabilitation). We record magnetoencephalographic (MEG) signals from stroke patients to examine cortical reorganization corresponding to improved motor and sensory performance of the paretic limb (Fig. 4). We also investigate the plasticity of neural network underlying recovery of brain function using animal models.

Recent Publications1. Tominaga, W., Matsubayashi, J., Deguchi, Y., Minami, C., Kinai, T., Nakamura, M., Nagamine,

T., Matsuhashi, M., Mima, T., Fukuyama, H., Mitani, A. (2009) A mirror reflection of a hand modulates stimulus-induced 20-Hz activity. Neuroimage 46: 500-504.

2. Kinai, T., Matsubayashi, J., Minami, C., Tominaga, W., Nakamura, M., Nagamine, T., Matsuhashi, M., Mima, T., Fukuyama, H., Mitani, A. (2009) Modulation of stimulus-induced 20-Hz activity during lower extremity motor image. Neurosci Res 64: 335-337.

3. Sano, M., Futaki, T., Kobashi, R., Teranishi, K. (2006) Abnormal eye movement patterns on a 2-point alternate fixation task and a routes finding task in unilateral spatial neglect. Jpn. J. Occupational Therapy 25: 322-333.

4. Toichi M, Findling RL, Kubota Y, Calabrese, JR, Wiznitzer M, McNamara NK, Yamamoto K. (2004) Hemodynamic differences in the activation of the prefrontal cortex: Attention vs. higher cognitive processing. Neuropsychologia 42: 698-706.

5. Toichi M, Kamio Y, Okada T, Sakihama M, Youngstrom EA, Findling RL, Yamamoto K. (2002) A lack of self-consciousness in autism. American Journal of Psychiatry 159: 1422-1424.

❶ What do you interpret the picture relevant to “person-environment-occupat ion”? How do you make an approach the complexity and multiple interactions from cognitive neuroscientific perspective?

❷ Optical imaging system using near-infrared spectroscopy.

The optical technique enables us to non-invasively measure hemodynamic changes in cerebral cor tex under naturalistic conditions.

❸ Changes of hemoglobin concentration in the prefrontal cortex.

T h e f i g u r e s h ow s c h a n g e s o f hemoglobin variables due to cognitive processing (mathematical reasoning).

❹ Equivalent current dipole location of motor fields during extension of the right thumb (MEG study).

❺ Laboratory members.

Clinical Cognitive NeuroscienceProfessor : Toshiko Futaki, Motomi Toichi, Akira Mitani Assistant Professor : Hiroshi Sakai, Jun Matsubayashi List for Tel, Fax & E-Mail : See page 000-000

Clinical Cognitive Neuroscience

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- Rehabilitation Sciences - Occupational Therapy


“Brain Function and Rehabilitation” is a new occupational therapy program established in Graduate School of Medicine, Human Health Science Department in 2007. It is an academic program, the purpose of which is to bring together the knowledge and the art regarding rehabilitation, from the view point of “interaction between human functioning and the environment”. We research on the ways to support the persons with mental dysfunction and developmental disorders to control their lives and adjust to the environment. As the basis of our research, we adopt medical and psychological assessment methods, such as motor function assessment, mental processing assessment, and information regarding the relation between the disease and the disability.

Hiroshi Yamane, OTR, Ph.D. Professor

Research and EducationIn “Brain Function and Rehabilitation” program, we carry out clinical research, education and clinical guidance, regarding techniques and methodology to facilitate rehabilitation and development of the central nervous system. The subjects of our practice are problems caused by functional or organic dysfunction of the central nervous system (including developmental disorders) such as mental disorder, brain function disorder caused by brain injury, and developmental disability. Our clinical fields are hospitals, day care centers, rehabilitation facilities, and schools. Let’s think, for instance, what differences in the brain or the body makes a person capable or incapable to imitate another person’s movement? Occupational therapy in brain function rehabilitation is a process of communication between the person, the person’s body and the occupation. We study the interaction between the brain, body and the environment which occurs during carrying out the occupation, and utilize the results for early rehabilitation, supporting development, daily lives and education of the disabled people.

Clinical research and education in mental function field : Our research and educational interests are the occupational therapy, medical and social models of disability, the acute occupational therapy system, and supporting participation in the society, for people with mental dysfunctions such as psychiatric disorders, pervasive developmental disorders, and higher brain dysfunction.Clinical research and education in developmental field : Our research and educational interests are supporting adjustment to the environment, occupational therapy in educational settings, etc. The subjects of our practice are children with developmental disorders such as cerebral palsy, autism, learning disability, attention deficit/hyperactivity disorder, Asperger disorder.

Recent Publications1. Yamane H:History and current state of Japanese psychiatric occupational therapy. Journal of

Korean Association of Occupational Therapists:2010 2. 山根　寛 :心身統合の喪失と回復－コミュニケーションプロセスとしてみる作業療法の治療機序 .作業療法 ,27:73-82:2008

3. 山根　寛 :コミュニケーションとしての作業・身体 ,作業療法 ,25: 393-400:2006 4. 山根　寛 ,腰原菊恵 ,岩佐順子 :急性期精神科作業療法の役割と課題－医学部附属病院精神科神経科における試みより .精神科救急 ,12:18-23:2009

5. Yamane H, Kinoshita T: An interactional model of mental disability based on the international classification of functioning and　disability (ICIDH-2). Asian Journal of Occupational Therapy, 1:1-11:2001

6. 加藤寿宏 ,山田孝 :子どもは自分の運動能力をどのくらい正確に把握しているのか？ .作業療法 29:73-82:2010

7. 加藤寿宏 ,山田孝：現在の子どもの人物画－日本版ミラー幼児発達スクリーニング検査およびグッドイナフ人物画検査の標準化データとの比較検討－ .作業療法 29:743-753:2010

8. 第十麻紀 ,小林圭 ,加藤寿宏 ,新井紀子 ,松島佳苗 :通常の学級における特別支援教育を必要とする児童への作業療法の効果 .作業療法 ,28:510-515:2009

9. 加藤寿宏 :発達障害における連携と工夫－子どもを支える家族との連携－ .臨床作業療法5:214-218:2008

❶ Associate professor Kato: Presentation ❷ Clinical research of Sensory Integrative Intervention ❸ Development of Japanese version Sensory Integration Test ❹ NIRS measurement of brain function when acting ❺ Laboratory member

Brain Function and RehabilitationProfessor : Hiroshi Yamane Associate Professor : Toshihiro Kato Instructor : New hire Assistant : Michiyo Uehara List for Tel, Fax & E-Mail : See page 000-000


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- Rehabilitation Sciences - Occupational Therapy


In this unit we study about the construction of practical medical system, machinery development, various patient management based on social needs, medical needs, patient needs which will be done by uniting the knowledge of nursing/laboratory medicine/physical-occupational therapy courses as well as utilizing medicine-mechanic cooperation and product government college cooperation. Through the research and education in this unit we will bring up the health professionals who have wide knowledge of human health science, provide appropriate information to society, propose at various clinical settings based on their knowledge, and can show leadership in medical care teams.

Hidenori AraiProfessor

Research and EducationIn this fusion unit we are trying to construct medical care systems in which patients, elderly or handicapped people can live in peace. For this purpose we try to conduct interdisciplinary studies through the interaction of nursing, laboratory medicine, physical/occupational therapy courses, where we can sometimes utilize medicine-mechanic cooperation and product government college cooperation.Our research themes are the following:

1. To build a new health care system in an aged society2. To establish how to prevent the decline of ADL in frail elderly collaborated with comprehensive support centers in the community3. Research on the effect of discharge planning on QOL of a patient and their family and on the education tools for medical staffs collaborated with Department of Community Network and Collaborative Medicine, Kyoto University Hospital 4. Effect of comprehensive geriatric assessment (CGA) during hospitalization on ADL and QOL after discharge

Through these research projects we are also aiming to bring up various kinds of outstanding health professionals who can develop leading-edge medical technology, promote a new research field, participate in policy making for health care, and play a role as a super coordinator showing leadership among health professionals.

Recent Publications1. Yamada M, Aoyama T, Arai H, Nagai K, Tanaka B, Uemura K, Mori S, Ichihashi N, Dual-task walk

is a reliable predictor of falls in robust elderly adults. J Am Geriatr Soc 59: 143-164, 2011 2. Arai H, Yamamoto A, Matsuzawa Y, Saito Y, Yamada N, Oikawa S, Mabuchi H, Teramoto T, Sasaki

J, Nakaya N, Itakura H, Ishikawa Y, Ouchi Y, Horibe H, and Kita T. Prevalence of the Metabolic Syndrome in elderly and middle-aged Japanese. J Clin Geriat Gerontol, 1: 42-47, 2010

3. Arai H, Hiro T, Kimura T, Morimoto T, Miyauchi K, Nakagawa Y, Yamagishi M, Ozaki Y, Kimura K, Saito S, Yamaguchi T, Daida H, Matsuzaki M. More Intensive Lipid Lowering is associated with Regression of Coronary Atherosclerosis in Diabetic Patients with Acute Coronary Syndrome -Sub-analysis of JAPAN-ACS study- J Atheroscler Thromb, 17: 1096-1107, 2010.

4. Miyake KK, Nakamoto Y, Mikami Y, Ishizu K, Saga T, Higashi T, Togashi K. F-18 FDG PET of foreign body granuloma: pathologic correlation with imaging features in 3 cases. Clin Nucl Med. 35: 853-7, 2010.

5. Suga T, Nakamoto Y, Saga T, Higashi T, Hara T, Ishizu K, Nishizawa H, Togashi K. Prevalence of positive FDG-PET findings in patients with high CEA levels. Ann Nucl Med. 24:433-9, 2010.

Innovation Unit for Near Future System and TechnologyProfessor : Hidenori Arai Associate Professor : Kouichi Ishizu List for Tel, Fax & E-Mail : See page 000-000

Innovation Unit for Near Future System and Technology

- Fusion Unit for Near Future Human Health Sciences


Department ContactsN

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Basic Nursing Science

Environmental Health Nursing

Professor : Sawako Suga, C.C.P., Ph.D.TEL&FAX: +81-75-751-3961 e-mail: [email protected] Professor : Tomoko Wakamura, R.N., P.H.N., Ph.D.TEL&FAX: +81-75-751-3974 e-mail: [email protected] Professor : Kazuyo Suzuki, R.N., P.H.N., M.A.TEL&FAX: +81-75-751-3927 e-mail: [email protected]


Professor : Yumi Saito TEL&FAX: +81-75-751-3920 e-mail: [email protected] : Shinichi NomotoTEL: +81-75-751-3919 e-mail: [email protected] Professor : Momoe UtsumiTEL&FAX: +81-75-751-3927 e-mail: [email protected]

Clinical Nursing Science


Professor : Kiminori HosodaTEL: +81-75-751-3922 e-mail: [email protected] Associate Professor : Ikumi HondaTEL: +81-75-751-3928 e-mail: [email protected] Professor : Hiromi SakudaTEL: +81-75-751-3954 e-mail: [email protected] Professor : Sayaka TakenouchiTEL&FAX: +81-75-751-3947 e-mail: [email protected]

Psychiatric Nursing Professor : Shigeru SakurabaTEL&FAX: +81-75-751-3967 e-mail: [email protected] Professor : Nami KonishiTEL: +81-75-751-3947 e-mail: [email protected]

Critical Care NursingAssociate Professor : Chiharu Akazawa TEL&FAX: +81-75-751-3926 e-mail: [email protected] Associate : Risa FukudaTEL: +81-75-751-3947 e-mail: [email protected]

Family Nursing Science


Professor : Machiko Suzuki TEL&FAX: +81-75-751-3933 e-mail: [email protected]://www.hs.med.kyoto-u.ac.jp/childcare/Assistant Professor : Kanako KiyokawaTEL: +81-75-751-3971 e-mail: [email protected]

Midwifery & Women’s Health

Professor : Kiyoko KabeyamaTEL&FAX: +81-75-751-3972 e-mail: [email protected] Professor : Keiko YagiTEL: +81-75-751-3916 e-mail: [email protected] Professor : Yoko ChibaTEL: +81-75-751-3971 e-mail: [email protected]

Female Life-Cycle Nursing

Professor : Nobuhiko SuganumaTEL: +81-75-751-3912 e-mail: [email protected] Professor : Hatsumi TaniguchiTEL: +81-75-751-3925 e-mail: [email protected] Professor : Kotomi YamaguchiTEL: +81-75-751-3971 e-mail: [email protected]

Community Health and Community Health Nursing

Preventive Nursing

Professor : Toshiki Katsura , R.P.H.N. , R.N. , Ph.D.TEL: +81-75-751-3941 FAX: +81-75-751-3909 e-mail: [email protected] Lecturer : Mika OkuraTEL: +81-75-751-3960 e-mail: [email protected] Assistant Professor : Kanae Usui , R.P.H.N. , R.N. , M.N.Sc.TEL: +81-75-751-3927 FAX: +81-75-751-3909e-mail: [email protected]

Home Healthcare Nursing

Professor : Ayae Kinoshita TEL&FAX: +81-75-751-3969 e-mail: [email protected] Professor : Masakazu KubotaTEL&FAX: +81-75-751-3927 e-mail: [email protected]

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Medical Laboratory Science

Basic Laboratory Science

Professor : Shogo OkaTEL&FAX: +81-75-751-3959 e-mail: shogo@@hs.med.kyoto-u.ac.jp Professor : Kuniaki SaitoTEL&FAX: +81-75-751-3957 e-mail: [email protected]:http://www.hs.med.kyoto-u.ac.jp/saito-k/Associate Professor : Masaki IkemotoTEL: +81-75-751-3945 e-mail: [email protected] Professor : Yasuko YamamotoTEL: +81-75-751-3938 e-mail: [email protected]

List for Tel, Fax & E-Mail – Human Health Science –


Department Contacts

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Medical Laboratory Science

Innovational Laboratory Medicine

Professor : Tetsuya TakakuwaTEL: +81-75-751-3956 e-mail: [email protected] Professor : Kentaro Ibuki TEL: +81-75-751-4178 e-mail: [email protected]

Applied Laboratory Science

Professor : Souichi AdachiTEL: +81-75-751-3949 e-mail: [email protected] : Akihiko NakaizumiTEL: +81-75-751-3921 e-mail: [email protected] : Masatoshi FujitaTEL: +81-75-751-3932 e-mail: [email protected] Professor : Hiroshi ItohTEL: +81-75-751-3938 FAX: +81-75-751-3909e-mail: [email protected]

Information Technology and Medical Engineering

Medical Devices for Diagnoses

Professor : Akitoshi SeiyamaTEL&FAX: +81-75-751-3915 e-mail: [email protected] Professor : Satoshi SasayamaTEL: +81-75-751-3940 e-mail: [email protected]


Professor : Naozo SugimotoTEL: +81-75-751-4993 e-mail: [email protected] Professor : Tomohiro UenoTEL: +81-75-751-3938 FAX: +81-75-751-3909e-mail: [email protected]


Professor : Tsuyoshi ShiinaTEL: +81-75-751-4998 e-mail: [email protected]: http://www.hs.med.kyoto-u.ac.jp/shiina-lab/Associate Professor : Kenichi OtsukaTEL: +81-75-751-3942 FAX: +81-75-751-3909e-mail: [email protected]

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Physical Therapy, Rehabilitation Sciences

Motor Function Analysis

Professor : Hiroshi Kuroki, PT, PhDTEL: +81-75-751-3963 e-mail: [email protected] : Makoto IshibashiTEL: +81-75-751-3950 e-mail: [email protected] Lecturer : Koji OhataTEL: +81-75-751-3918 e-mail: [email protected] Lecturer : Yuko MaedaTEL: +81-75-751-3917 e-mail: [email protected] Professor : Tome Ikezoe, PT, PhDTEL: +81-75-751-3964 FAX: +81-75-751-3963e-mail: [email protected]: http://www.hs.med.kyoto-u.ac.jp/ghs/research-domain/reha-science-aoms/index.html

Development and Rehabilitation of Motor Function

Professor : Noriaki IchihashiTEL: +81-75-751-3951 e-mail: [email protected] : TadaoTsuboyamaTEL: +81-75-751-3948 e-mail: [email protected] Professor : Tomoki AoyamaTEL: +81-75-751-3952 e-mail: [email protected] Professor : Hiroshige TateuchiTEL: +81-75-751-3964 e-mail: [email protected] Professor: Minoru YamadaTEL: +81-75-751-3964 e-mail: [email protected]

Occupational Therapy

Clinical Cognitive Neuroscience

Professor : Toshiko FutakiTEL: +81-75-751-3958 e-mail: [email protected] : Motomi ToichiTEL: +81-75-751-3966 e-mail: [email protected] : Akira Mitani TEL: +81-75-751-3913 e-mail: [email protected] Professor : Hiroshi SakaiTEL: +81-75-751-3913 e-mail: [email protected] Professor : Jun Matsubayashi TEL&FAX: +81-75-751-3965 e-mail: [email protected]


Professor : Hiroshi YamaneTEL: +81-75-751-3943 e-mail: [email protected] Professor : Toshihiro Kato TEL: +81-75-751-3819 FAX: +81-75-751-3909e-mail: [email protected]

Fusio

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and Technology

Professor : Hidenori AraiTEL&FAX: +81-75-751-3861 e-mail: [email protected] Professor : Kouichi IshizuTEL: +81-75-751-3939 e-mail: [email protected]


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Graduate School of Medicine Kyoto University 2011