Research Project
2150839
Excessive infiltration of lymphocytes has been implication in the pathogenesis of several inflammatory conditions, including inflammatory bowel disease (IBD). The mucosal vascular addressin, MAdCAM-1 is a tissue specific adhesion receptor selectively expressed in high endothelial venules (HEVs) in mucosal lymphoid tissues including Peyer's patches and, to a lesser extent, small venules in the lamina propria. Cell adhesion assays and in vitro homing experiments have shown that the alpha4beta7 integrin, expressed on both B and T cell subsets, defines a mucosal homing receptor which preferentially interacts with MAdCAM-1. Preliminary immunocytochemistry has shown lymphocytic infiltrates expressing alpha4beta7 and increased expression of MAdCAM-1 in intestinal tissues of murine models of IBD and similar lymphocyte infiltrates in human tissue as well. Recently developed murine models of IBD will provide a key step in development of therapeutic strategies to inhibit these receptor-counter receptor interactions which have been implicated in the etiology of IBD. Furthermore, a high throughput drug screen will be set up to identify and develop small molecule antagonists of these receptors. This proposal will therefore lay the foundation for a new class of anti inflammatory drugs. PROPOSED COMMERCIAL APPLICATION: In vivo studies will provide the basis of understanding the involvement of mucosal adhesion receptors in inflammatory bowel disease and we will set up drug screening to identify novel small molecule antagonists of these receptors.
