Lung Research – future directions for LIWA

Yuben Moodley

INTRODUCTION

• If you think about the following diseases: • COPD, emphysema, asthma, cystic

fibrosis, lung cancer, bronchiectasis, asbestosis, lung fibrosis, sarcoidosis

• You will appreciate that 1 in 4 Australians have lung disease

INTRODUCTION

• COPD-emphysema and bronchitis by 2020 will be the 3rd commonest cause of global morbidity and mortality.

• If you add certain infections such as TB then lung disease is a major global crisis

INTRODUCTION

The surface area of the lung is 70m2

10 000l/day of air

Oxygen consumption 250 to 5500 ml/min

Pulmonary blood flow 4 to 40l/min

LUNG DISEASE THE SILENT SUFFERERS

• Short of breath - you withdraw

• These people need advocates

The Lung Institute of WA (LIWA) Our aims

– Support high quality research into the treatment and management of lung diseases.

– Support research into associated conditions.

– Improve the well-being of patients.

– Support the careers of young scientists.

– Provide a strong educational and scientific resource for the community.

– Be an advocacy group for better lung health.

THE ALGORITHM OF DISEASE Genetics, epigenetics Injury

Inflammation

Normal repair and regeneration

Impaired/pathological repair

Fibrosis cancer

Chronic lung disease

THE ALGORITHM OF DISEASE Genetics, epigenetics Injury/Infection

Inflammation

Normal repair and regeneration

Impaired/pathological repair

Fibrosis cancer

Chronic lung disease

GENETICS Prof Philip Thompson Dr Svetlana Baltic

PLEURAL Prof Gary Lee

TISSUE REPAIR GROUP Prof Steven Mustsaers A/Prof Cecilia Prele STEM CELL

A/Prof Yuben Moodley

CLINICAL TRIALS UNIT Prof Philip Thompson CYSTIC FIBROSIS Dr Siobhan Mulroonan PHYSIOTHERAPY A/Prof Sue Jenkins ADVANCED LUNG Prof Eli Gabbay

Asthma, COPD

FUNDING STRATEGY

• Cutting edge research

• Collaboration

• Community engagement

COLLABORATION

WESTERN AUSTRALIA AUSTRALIA INTERNATIONAL

THE THREE PICTURE RATING

Molecular Genetics and Inflammation Unit

Genetics, epigenetics Injury/Infection

Inflammation

Normal repair and regeneration

Impaired/pathological repair

Fibrosis cancer

Chronic lung disease

GENETICS Prof Philip Thompson Dr Svetlana Baltic

Asthma, COPD

Molecular Genetics and Inflammation Unit

Why? Current treatments are not effective for everyone How? • use of LIWA cohort of over 1200 asthmatics with the largest cohort of severe asthmatics

•Genotyping of ADRβ2 polymorphisms

•Investigating pharmacogenetic effect of ADRβ2 polymorphisms on receptor expression and activation in the presence or absence of ADRβ2 agonists (eg. Ventolin)

PERSONALIZED TREATMENT FOR ASTHMA

Molecular Genetics and Inflammation Unit

Developing New Treatments for Lung Diseases

ASTHMA COPD

BRONCHIECTASIS CYSTIC FIBROSIS

• Identifying new molecular targets

• Generating more effective treatments

• Halting disease progression

• Inhibition of the cycle of chronic inflammation

Big cohort of patients with inflammatory airway diseases

Molecular Genetics and Inflammation Unit

1) Genotyping and association studies, – Australian Genetic Consortium, National International

Collaborations Publications (Nature Genetics, Lancet, etc) Pharmaceutical Companies

2) Explore different strategies of modifying gene expression – CRC for Asthma and Airways, National Multicentre Collaboration – Patient, publications

3) Research in the field of pharmacogenetics, – University of Adelaide, Brisbane

4) Discover molecular mechanisms of gene regulation, splicing and expression – Local and National, potential for International Collaborations

TISSUE REPAIR GROUP Genetics, epigenetics Injury/Infection

Inflammation

Normal repair and regeneration

Impaired/pathological repair

Fibrosis cancer

Chronic lung disease

TISSUE REPAIR GROUP Prof Steven Mustsaers A/Prof Cecilia Prele

Asthma, COPD

TISSUE REPAIR GROUP IDIOPATHIC PULMONARY FIBROSIS (IPF)

TISSUE REPAIR GROUP

GP130

STAT 3 MAPK

INCREASED LUNG FIBROSIS

PROTECTIVE AGAINST LUNG FIBROSIS

STAT3 regulation of cell responses in IPF

TISSUE REPAIR GROUP

LUNG FIBROSIS IL-6/gp130/STAT signalling in the pathogenesis of pulmonary fibrosis. The role of the epithelium in regulating B cell activity (G Laurent, G Hoyne, M Ernst, R O’Donoghue)

SOCS-mediated regulation of STAT signalling in IPF BARD-1 in the pathogenesis of lung fibrosis (G Laurent and I Irminger-Finger) Role of Fibulin-1 in IPF (J Burgess and J Black)

MESOTHELIOMA Collagen/TGF-β signalling in mesothelioma (G Laurent, R McAnulty) MiRNAs in mesothelioma: diagnostic and biological role (W Musk G Reid, M Kirschner, J Creaney, B Robinson, G Lee) Hedgehog signalling pathway in mesothelial repair and the pathogenesis of mesothelioma: mutations, mechanisms, therapeutics (N Watkins, A Nowak) BARD-1 in the pathogenesis of mesothelioma (I Irminger-Finger)

Plasticity of mesothelial cells (R Dilley)

PLEURAL GROUP Genetics, epigenetics Injury/Infection

Inflammation

Normal repair and regeneration

Impaired/pathological repair

Fibrosis cancer

Chronic lung disease

PLEURAL Prof Gary Lee

Asthma, COPD

PLEURAL GROUP

CLINICAL PLEURAL SERVICE

PATIENT BASED RESEARCH

LABORATORY RESEARCH

PLEURAL GROUP

PLEURAL GROUP

New Molecular Targets

Novel Concepts for Fluid Control

MALIGNANT PLEURAL EFFUSION

MPM Gene Profiling

IPC complication studies

Phase III: IPC vs Talc

Novel Biomarkers

WA MPE study

PLEURAL GROUP

Murine model Open label Follow-up

MIST-2

Animal Model Clinical Trials

PLEURAL INFECTION

In vitro

Bacteria on mesothelial cells

PLEURAL GROUP

WA NETWORK ASIA-PACIFIC NETWORK

STEM CELL Genetics, epigenetics Injury/Infection

Inflammation

Normal repair and regeneration

Impaired/pathological repair

Fibrosis cancer

Chronic lung disease

STEM CELL A/Prof Yuben Moodley

Asthma, COPD

STEM CELL

STEM CELL GROUP-CYSTIC FIBROSIS

CFTR gene mutations

CFTR dysfunction

Altered ion transport Loss of ASL, thick viscous secretions and impaired mucociliary clearance

Chronic bacterial infection

Chronic inflammation and fibrosis

Bronchiectasis, pulmonary hypertension and cor pulmonale

STEM CELL GROUP

Figure 1. Pathogenesis of CF. In the normal airway (A), Sodium is absorbed by the cell and Chloride (Cl) is secreted by the CFTR. In CF the CFTR is defective which results in no secretion of Cl into the airway. This results in increased absorption of Na, paracellular absorption of Cl and water resulting in a reduction of the air surface liquid (ASL).

normal Cystic fibrosis

STEM CELL GROUP

WA NETWORK Cell and tissue therapy centre of WA (Dr Marian Sturm) Human studies in COPD CCTRM-Geoff Laurent CYSTIC FIBROSIS-Steve Stick and Anthony Kicic

LARGE ANIMAL MODELS VENTILATED PIG AND STEM CELLS-Manitoba (Dr Ruth Mcgrath) REPROGRAMING-pluripotent cells to lung epithelium-Barcelona-Dr Michael Edel- CYSTIC FIBROSIS-North Carolina-Dr Robert Tarran

CLINICAL TRIALS/CLINICAL SCIENCES GROUP

Genetics, epigenetics Injury/Infection

Inflammation

Normal repair and regeneration

Impaired/pathological repair

Fibrosis cancer

Chronic lung disease

CLINICAL TRIALS UNIT Prof Philip Thompson CYSTIC FIBROSIS Dr Siobhan Mulroonan PHYSIOTHERAPY A/Prof Sue Jenkins ADVANCED LUNG Prof Eli Gabbay

Asthma, COPD

• Clinical trials allow recruitment of patients for research

• Education of patients • Brings cutting edge technology and the

latest therapies to patients • Income • Trials in asthma and COPD

CLINICAL TRIALS/CLINICAL SCIENCES GROUP

LIWA-COMMUNITY ENGAGEMENT

Medical Research Seminar Series

Delirium 24-Hour Cycle Race

The Search for Perth’s Best Set of Lungs

HBF Run for a Reason

Flu Vaccination Clinic

Cook for a Cure

Chevron City to Surf

Corporate lung testing

Melbourne Cup Luncheon

World COPD Day lung testing Members’ functions

Cook for a Cure

Delirium 24-hour cycle race

Melbourne Cup Luncheon

The Search for Perth’s Best Set of Lungs

LIWA-COMMUNITY ENGAGEMENT

LIWA Grants – The Alan King Westcare Grant – The LIWA Glenn Brown

Memorial Grant – The LIWA Sarcoidosis and

Other Granulomatous Lung Diseases Project Grant

Scholarships

– PhD – Honours – Summer Vacation Cadetships

Awards

– Junior and Senior travel awards

Funds raised for the LIWA Glenn Brown Memorial Grant

OPPORTUNITES FOR COLLABORATION

• Personalized medicine • Biomarkers for diagnosis and preventative

medicine • Reversing tissue remodeling (scar) • Replace scar tissue with healthy tissue • Curing cancer

OPPORTUNITES FOR COLLABORATION

• Large animal models • Human organs for experimentation-long

term preservation • Signal transduction • Genetic and epigenetic regulation of

disease • Gene and cell delivery to the human lung • Novel imaging of disease processes