The inflammatory bowel diseases (IBD;Crohn's disease, ulcerative colitis) are idiopathic inflammatory disorders of the intestine and/or colon in which active disease is characterized by the presence of large numbers of leukocytes (e.g. PMNs, monocytes, and lymphocytes) in the intestinal and/or colonic interstitium co-incident with extensive tissue injury including edema, loss of goblet cells, erosions and ulcerations. The overall objectives of this PPG are: 1) to define the role of the intestinal circulation towards the induction and perpetuation of chronic gut inflammation, and 2) to elucidate the cellular, immunological and physiological mechanisms that underlie the contributions of the vasculature to the pathogenesis of experimental IBD. The work outlined in this PPG is a natural extension of the research interests and ongoing collaborative efforts of seven investigators with active programs in the areas of mucosal immunology, endothelial cell biology, intestinal inflammation, and the microcirculation. Support is requested for four projects, two scientific cores and one administrative core. A shared objective of the four research projects outlined in this renewal application is to define how the vasculature modulates the induction and progression of acute and chronic gut inflammation. Project 1 will define the vascular and immunological mechanisms responsible for T-cell trafficking to the Peyer's patches (PPs) and/or mesenteric lymph nodes (MLNs) and to the gut. Special emphasis will be placed on the interactions between T-cells and vascular endothelial cells in gut-associated lymphoid tissue and colon. Project 2 will investigate the immunological and physiological mechanisms responsible for the remarkable vasocontriction and consequent reductions in colonic blood flow observed prior to the onset of inflammation. Project 3 will focus on the role of the different natural anticoagulant mechanisms in the pathogenesis of experimental colitis and define the mechanisms by which the hypercoaguable state associated with gut inflammation acts to amplify the inflammatory response as well as enhance the vulnerability of the microvasculature in distant tissues to thrombosis formation. Project 4 will investigate the role of angiogenesis in the pathophysiology of chronic gut inflammation. This project will focus on the molecular, cellular and immunological mechanisms that drive angiogenesis in the chronically inflamed bowel and define the pathways by which this process propagates colonic inflammation. These projects will be supported by services provided by an Administrative Core (Core A), an Animal Models Core (Core B) and a Histopathology Core (Core C).
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