Mechanism of regulation of Down Regulated Adenoma (DRA) in obesity associated colitis induced colon cancer

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Obesity has been associated with increased risk and early onset of colon cancer. About 40% of obesityrelated cancer incidences were recorded in the United States. More specifically in West Virginia, 49% of obesity-associated incidences of colon cancer and 18% of associated mortality rate have been documented. Similarly, inflammatory bowel disease (IBD) (ulcerative colitis (UC) and Crohn’s disease (CD)) is known to be an important risk factor for the development of colon cancer, namely colitis-associated colon cancer (CAC). CAC is preceded by clinically detectable IBD. UC increases CAC risk up to 18-20% while CD contributes up to 8% after 30 years of active disease. It has been demonstrated in the colon in an in vivo genetic obesity model (Zucker rats) and in in vitro in Adipocyte Derived Secretome (ADS) model of obesity that chloride absorption is mediated by the Cl-/HCO3- exchanger DRA was significantly decreased. Similarly, in a rat model of colitis and in CAC, DRA was downregulated. This indicates that alteration of regulation of chloride absorption is a common factor in both obesity and colon cancer models. However, if downregulation of DRA mediated chloride absorption might specifically be responsible for the onset and progression of obesity or colitis-associated colon cancer is not known. Therefore, we hypothesized that the downregulation of Cl-/HCO3- exchanger DRA in colon in obesity or in colitis increases the risk of colon cancer onset and progression. The overall aim of the proposed project is to determine the mechanism of regulation of Cl-/HCO3- exchange in the colon in obesity and colitis mediated colon cancer. To decipher this, a Zucker rat genetic model of obesity and colitis-associated colon cancer will be used. These animal models will be used to induce colon cancer with DSS and Azoxymethane to determine the functional and molecular mechanism of the regulation of DRA in obesity and colitis-associated colon cancer. Following will be the specific aims of this proposal. Specific Aim 1: To Determine the mechanism of regulation of DRA in the colon during obesity. Specific Aim 2: To Define the regulation of DRA in obesity mediated colon cancer. Specific Aim 3: To Determine the mechanism of regulation of DRA in colitis during obesity. Specific Aim 4: To Delineate the mechanism of regulation of DRA in colitis-associated colon cancer during obesity. This proposal will indeed address the lacunae in the understanding of downregulation of DRA, which may play a critical role in the pathogenesis of obesity, obesity-associated colon cancer, colitis and CAC. Successful completion of these studies as a COBRE ACCORD investigator will provide the necessary training and generation of preliminary data to compete for an NIH R01 and become an independent investigator.