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 receptors and cytokines, an amplification phase regulated through the cell cycle, and a downregulatory 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 of 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 with be tested through four specific aims: (1) Characterization of T-cell receptor-mediated activation: (2) Characterization of cytokine-mediated T-cell activation: (3) Analysis of T-cell cycle regulation: (4) Investigation of the mechanisms of T-cell apoptosis. The cellular and molecular elements, and the experimental systems 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.
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