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