CONTRACTILE SIGNAL TRANSDUCTION IN ULCERATIVE COLITIS

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DESCRIPTION (provided by applicant): Ulcerative colitis is a chronic inflammatory condition affecting the large bowel: Although it is most frequent in the rectosigrnoid area, it may involve the whole colon. Inflammation in ulcerative colitis is histologically limited to the mucosa, and its effects have been better characterized in the superficial than in the deeper layers such as muscularis propria. Inflammation, however, may affect the muscle layer, leading to motor dysfunction, which contributes to key clinical symptoms, including diarrhea, constipation, and crampy abdominal pain. To define inflammation, associated changes in motor function we will examine the circular muscle from the sigmoid colon from patient with active ulcerative colitis and compare it with muscle from disease-free margins of histologically normal colon tissue from cancer resections. The sigmoid is most often involved and frequently resected, and this avoids variations associated with different anatomical locations of the disease. In preliminary experiments, we find that inflammatory mediators such as interleukin-1beta and hydrogen peroxide are present in the muscularis propria. Our central hypothesis is that inflammatory mediators, first produced by inflammatory cells in the mucosa, may induce production of additional mediators by the target cells themselves, and that in time the muscularis propria becomes affected leading to motor disturbances. We therefore propose to: A) Define inflammation-induced changes in contractile signal transduction pathways of human sigmoid colon. B) Test the effect of selected inflammatory mediators, known to be present in ulcerative colitis mucosa, to determine their individual contribution to the observed changes in colonic motor function. C) Determine whether inhibition of selected inflammatory mediators may reverse inflammation-mediated changes in colonic motor function. Examining the relationship between inflammatory mechanisms and changes in motor function may help in understanding the functional disturbances associated with ulcerative colitis and identifying new targets for therapeutic intervention.