Torunn Bruland; post doc NTNU, DMF

Gene regulation in biological responses:Focus on gastrin responses in neuroendocrine cells in the gastro-intestinal tract

Viral determinants for pathogenesis and the influence of sex on the susceptibility to

Friend murine leukaemia virus infection

Studies of early retrovirus-host interactions

ANIMAL MODEL (mice)

• virology • immunology• cell biology• signal transduction• molecular biology• statistic

Dr. philos thesis 2003; NTNU, Faculty of Medicine

BIOMEDICAL PROBLEM

SCREENINGgenome-widesystem-wide

HYPOTHESIS GENERATIONdata analysis

HYPOTHESIS TESTING

high throughput/single gene

Gene regulation in biological responses

Molecular mechanisms in the normal and diseased gastrointestinal system

Normal Early gastric cancer Adenocarsinoma

Gene regulation in biological responses:Focus on gastrin responses in neuroendocrine cells in the gastro-intestinal tract

IntroductionEnterochromaffin-like (ECL) cells are a

distinctive type of neuroendocrine cells in the gastric mucosa underlying the epithelium

Longer term stimulation of ECL cells by gastrin stimulates significant

proliferation of ECL cells

Several gastrin responsive genes contain

cAMP responsive promotor element (CRE)

Modulation of gastrin-mediated gene expression by transcriptional regulators of the CREB/CREM/ATF family

BIOMEDICAL PROBLEM

SCREENINGgenome-widesystem-wide

HYPOTHESIS GENERATIONdata analysis

HYPOTHESIS TESTING

high throughput/single gene

•gastric carsinoma•gastric carcinoids•hypergastrinemia

•gastrin-mediated gene expression•CREB/CREM/ATF-modulated gene expression

•Genome-wide gene expression

•gastric mucosa custom microarrays

•system-wide screening of CREB/CREM/ATF splice variants

Work plan: cDNA/oligo/splice variant MIKROARRAY

Generation of models

BIOMEDICAL PROBLEM

SCREENINGgenome-widesystem-wide

HYPOTHESIS GENERATIONdata analysis

HYPOTHESIS TESTING

high throughput/single gene

•gastric carsinoma•gastric carcinoids•hypergastrinemia

•gastrin-mediated gene expression•CREB/CREM/ATF-modulated gene expression

•Genome-wide gene expression

•gastric mucosa custommicroarrays

•system-wide screening ofCREB/CREM/ATF splice variants

statistical methods for: •preprocessing and discrimination and classification•rule-based methods for classification•optimal use of biological background knowledge

Hypothesis testing: high throughput/single gene

Reverse Transfection RNAi + Microarray

BIOMEDICAL PROBLEM

SCREENINGgenome-widesystem-wide

HYPOTHESIS GENERATIONdata analysis

HYPOTHESIS TESTING

high throughput/single gene

•gastrin-mediated gene expression•CREB/CREM/ATF-modulated gene expression

•Genome-wide gene expression

•gastric mucosa custom microarrays

•system-wide screening of CREB/CREM/ATF

•splice variants

statistical methods for: •preprocessing and discrimination and classification•rule-based methods for classification•optimal use of biological background knowledge

High throughput•96-well•array based

Single gene•knock-up•knock-down (RNAi)

animal models

Summary

BIOMEDICAL PROBLEM

SCREENINGgenome-widesystem-wide

HYPOTHESIS GENERATIONdata analysis

HYPOTHESIS TESTING

high throughput/single gene

Prosjektansvarlig Astrid Lægreid, professor, dr.scient.,

ProsjektmedarbeidereLiv Thommesen, førsteam.. dr.philos., HiSTTorunn Bruland, post.doc. dr.philos., IKM, NTNUOla Ween, post.doc. dr.scient., IKM, NFRKristine Misund, cand.scient. NTNUTonje Strømmen, siv.ing. NTNU

Gene regulation in biological responses:Focus on gastrin responses in neuroendocrine cells in the gastro-intestinal tract