The regulation of stellate cell fate in chronic pancreatitis. (360G-Wellcome-080486_Z_06_Z)

£208,936

In chronic inflammation resident pancreatic stellate cells proliferate and transform into myofibroblastic cells (activated PSC, aPSC) which produce the extracellular matrix of fibrosis. Our group has shown that agents which promote apoptosis of activated hepatic stellate cells are antifibrotic. Survival signals supporting aPSC might be good targets for antifibrotic therapy. The overall aim of this study is to examine factors that maintain survival of aPSC in CP, focusing on two candidates - tissue inhibitor of metalloproteinases (TIMPs) and insulin. A) Antiapoptotic effects of insulin and TIMP-1 on serum-deprived cultured rat aPSC will be examined using acridineorange and TUNEL staining of nuclei and cellular caspase-3 activity. Potential intracellular mediators of apoptosis to be examined using gene arrays. Expression studies and activity/reporter assays of NFkappa B will be undertaken. B) Mechanistic studies of the role of TIMP-1 in maintaining aPSC survival. We will compare both processes during development and resolution offibrosis in cerulein induced CP in normal versus TIMP-1 knockout mice. Fibrosis development and aPSC numbers and apoptosis will be assessed. C) Markers of apoptosis will be examined in thin sections of clinical samples of CP with mRNA expression examined using laser capture microdissection of aPSC then quantitative PCR.

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Grant Details

Amount Awarded 208936
Applicant Surname Patel
Approval Committee Clinical Interview Committee
Award Date 2006-12-07T00:00:00+00:00
Financial Year 2006/07
Grant Programme: Title Research Training Fellowship
Internal ID 080486/Z/06/Z
Lead Applicant Dr Manish Patel
Partnership Value 208936
Planned Dates: End Date 2011-10-31T00:00:00+00:00
Planned Dates: Start Date 2007-03-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East
Sponsor(s) Dr Robert Benyon