Crohn's disease and ulcerative colitis are clinically, immunologically and morphologically distinct forms of inflammatory bowel disease (IBD). The classic inflammatory response in ulcerative colitis patients is limited to the mucosa and submucosa. Yet, the colonic circular smooth muscle contractility is suppressed in these patients. The precise nature of the stimulus and the cellular mechanisms that suppress circular smooth muscle contractility in the absence of a clearly identified inflammatory response in the muscularis externa are not known. By contrast, transmural inflammation occurs in Crohn's disease. The circular smooth muscle contractility is suppressed also in these patients. Our overarching hypothesis is that different inflammatory mediators and cellular mechanisms suppress colonic circular smooth muscle contractility in the two forms of IBD. We will test this hypothesis in two well-established and validated animal models of inflammation, the trinitrobenzene sulfonic acid (TNBS) - induced colonic inflammation that mimics the classic features of Crohn's disease, and dextran sodium sulfate (DSS) - induced colonic inflammation that mimics those of ulcerative colitis.
Our specific aims are to investigate the: 1. Differential immune responses in the muscularis externa of the TNBS and DSS models and how the initial immune response in the mucosa sends the signal to the muscularis externa to initiate the immune response there.2. Cellular and molecular mechanisms by which the respective prominent inflammatory mediators in the muscularis externa of the TNBS and DSS models alter the expression of key cell signaling proteins in circular smooth muscle cells, which suppresses their contractility.3. Cis-regulation of genes encoding the proteins, whose suppression results in the reduction of cell contractility in the TNBS and DSS models of inflammation. The hypothesis, that motility dysfunction due to the suppression of circular smooth muscle contractility may result from different cellular and molecular mechanisms, is novel. Gut inflammation may occur due to a variety of bacterial, viral and parasitic infections as well as due to food allergies, and IBD. Colonic motility dysfunction is one of the major factors contributing to the common symptom of diarrhea in all types of inflammation. Our findings are expected to suggest that alternate therapeutic approaches may be required to normalize motility dysfunction in different types of inflammation. This situation is similar to that in the two forms of IBD;both of which develop inflammation, but their therapeutic approaches are different, because the nature of inflammatory responses in the ulcerative colitis and Crohn's disease patients are different.
Gut inflammation may occur due to a variety of bacterial, viral and parasitic infections as well as due to food allergies, and IBD. Colonic motility dysfunction is one of the major factors contributing to the common symptom of diarrhea in all types of inflammation. Our findings are expected to suggest that alternate therapeutic approaches may be required to normalize motility dysfunction in different types of inflammation.
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