A variety of immune abnormalities have been described in Crohn's disease (CD) and ulcerative colitis (UC), which have lead to substantial progress in the understanding of the pathogenesis of inflammatory bowel disease (IBD). Most of these abnormalities have been detected in studies of mucosal T-cell function, an approach limited by the non specific nature of cellular responses during chronic inflammation. T-cell function is mediated by a complex series of events involving an activation phase through T-cell receptor receptors and cytokines, an amplification phase regulated through the cell cycle, and a down- regulatory phase mediated by apoptosis. Thus, in order to better understand T-cell function in IBD, and perhaps uncover disease-specific abnormalities, it seems imperative to gain some insight into the molecular mechanisms governing mucosal T-cells. Through a collaborative effort with experts in IBD, mucosal immunity, T-cell biology, signal transduction mechanisms, cell cycle regulation, and apoptosis, and by focusing on selected events relevant to mucosal immunity and inflammation, we have generated compelling evidence for signaling and regulatory defects on mucosal T-cells in IBD. Based on this preliminary evidence, we propose to test the following central hypothesis: The signal transduction pathways of mucosal T-cell activation, growth and regulation are altered in IBD, and separate molecular abnormalities lead to distinct inflammatory responses in CD and UC. This central hypothesis will be tested through four specific aims: (1) Characterization of T- cell receptor-mediated activation; (2) Characterization of cytokine- mediated T-cell activation; (3) Analysis pf T-cell cycle regulation; (4) Investigation of the mechanisms of T-cell apoptosis. The cellular and molecular elements, and the experimental system necessary to perform the proposed studies are available, have been tested, and proved to be workable. We believe this proposal provides a novel conceptual framework that will allow a more detailed and mechanistic understanding of IBD pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
7R37DK030399-22
Application #
7030943
Study Section
Special Emphasis Panel (NSS)
Program Officer
Hamilton, Frank A
Project Start
1982-08-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
22
Fiscal Year
2006
Total Cost
$406,330
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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