This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Crohn's disease is an inflammatory bowel disease that affects between 400,000-600,000 people in North America. The Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxic effects of a large class of environmental contaminants including dioxins and PCBs. Little information is known about the role of the AhR in gut inflammation or inflammatory bowel disease. Therefore, the goal of the studies in this proposal is to elucidate the role of AhR activation in the development and progression of inflammation associated with Crohn's disease. The adverse effects of dioxin and dioxin-like chemicals that pollute the environment are predominantly mediated through the AhR, which is a cytosolic, ligand-activated transcription factor that can bind a variety of natural and synthetic compounds. Dioxin (TCDD) is the highest affinity ligand for this receptor and is resistant to metabolism. Since many immune cells express the AhR (either constitutively or following induction after cellular stimulation) and many genes involved in immunity and inflammation are modulated by AhR ligands, it is critical to understand how AhR activation can affect the function of the immune system. Although early reports suggested that TCDD exacerbates some inflammatory responses, more recent studies have defined cellular mechanisms for its potent immunosuppressive effects. In particular, regulatory T cells (Tregs) can be induced following TCDD exposure leading to potent suppression of adaptive immune responses. Inflammatory bowel disease (IBD), comprised of Crohn's disease and ulcerative colitis, is a chronic inflammatory state of the gastrointestinal (GI) tract. This disease typically affects young Caucasians that live in urbanized, developed countries. It is estimated that the average number of cases currently ranges from 100-200 cases per 100,000 individuals in North America, northern Europe, and the United Kingdom. Unlike ulcerative colitis, Crohn's disease affects all layers of the intestinal wall anywhere along the GI tract, but especially in the ileum and colon. Due to a severe inflammatory response, Crohn's disease patients experience many unpleasant intestinal symptoms, such as frequent diarrhea, abdominal pain, and rectal bleeding as well as potentially life-threatening extraintestinal complications. There is no known pharmaceutical or surgical cure for Crohn's disease. Treatment options are restricted to controlling symptoms, maintaining remission, and preventing relapse. Since Crohn's disease affects millions of Americans and arises in part from various environmental factors, it is important to study the mechanisms underlying this disease. Moreover, AhR activation can effectively modulate both immune and inflammatory responsiveness so studying the effects of environmental contaminants acting as AhR ligands on the generation of Crohn's disease is warranted. Therefore, the goal of the studies in this proposal is to elucidate the role of AhR activation in the development and progression of inflammation associated with Crohn's disease. The results of this project will provide novel information about gut mucosal immunity and the effects of environmental contaminants on an important segment of the immune system.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
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Special Emphasis Panel (ZRR1-RI-5 (01))
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University of Montana
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Schools of Pharmacy
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