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

下调腺瘤（DRA）在肥胖相关性结肠炎诱发结肠癌中的调节机制

• 批准号: 10651008
• 负责人: Balasubramanian Palaniappan
• 金额: $ 15.18万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651008
• 关键词: Acids; Address; Adipocytes; Adipose tissue; Affinity; Age; Animal Model; Animals; Anions; Appalachian Region; Azoxymethane; Back; Bicarbonates; Body Weight; Buffers; Caco-2 Cells; Calories; Cancer Model; Carbon Dioxide; Case Study; Cell Line; Cells; Centers of Research Excellence; Centrifugation; Chlorides; Clinical; Colitis; Colitis associated colorectal cancer; Colon; Colon Carcinoma; Complement; Complementary DNA; Control Groups; Crohn' s disease; Cytosol; Data; Data Analyses; Development; Diagnostic; Diet; Disease; Distal; Down-Regulation; Ensure; Experimental Models; Fatty acid glycerol esters; Felis catus; Filtration; Generations; Genetic Models; Genetic Transcription; Gluconates; Harvest; Human; Ice; Immunofluorescence Immunologic; In Vitro; Incidence; Incubated; Inflammatory Bowel Diseases; Kinetics; Liquid substance; Malignant Neoplasms; Manufacturer Name; Measures; Mediating; Membrane; Messenger RNA; Missouri; Modeling; Molecular; Obesity; Pathogenesis; Penicillins; Phenolsulfonphthalein; Play; Precipitation; Procedures; Proteins; Protocols documentation; Publishing; RNA; RNA purification; RNA-Directed DNA Polymerase; RNase protection assay; Radioactivity; Rattus; Reaction; Regulation; Research Personnel; Risk; Risk Factors; Role; Running; SLC26A3 gene; Saline; Sampling; Scintillation Counter; Secondary to; Serum; Sodium Chloride; Sodium Dextran Sulfate; Sprague-Dawley Rats; Sterility; Streptomycin; System; Techniques; Temperature; Thinness; Time; Tissues; Training; Ulcerative Colitis; United States; United States National Institutes of Health; Vesicle; Visceral fat; Water; West Virginia; Western Blotting; Zucker Rats; absorption; adenoma; apical membrane; base; beta Actin; colon cancer cell line; colon cancer risk; dextran sulfate sodium induced colitis; diet-induced obesity; dietary control; dosage; drinking water; early onset colon cancer; experimental group; experimental study; extracellular; in vitro Model; in vivo; inhibitor; mRNA Expression; mortality; nonlinear regression; novel; obesity genetics; oligo (dT); potassium bicarbonate; protein expression; response; subcutaneous; time interval; uptake

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.

肥胖与结肠癌风险增加和早期发病有关。约40%的肥胖与肥胖有关 美国的癌症发病率是有记录的。更具体地说，在西弗吉尼亚州，49% 与肥胖相关的结肠癌发病率和相关死亡率的18%一直是 有记录在案。同样，炎症性肠病(IBD)(溃疡性结肠炎(UC)和克罗恩病 (CD))是结肠癌发生的重要危险因素，即结肠炎相关 结肠癌(CAC)。临床上可检测到的IBD先于CAC。UC将CAC风险增加高达18%-20% 而CD在活动性疾病30年后的贡献率高达8%。它已经在一种结肠癌中得到了证实 体内遗传性肥胖模型(Zucker大鼠)和体外脂肪细胞源性分泌体(ADS)模型 氯离子/HCO3-交换体介导的肥胖DRA显著降低。 同样，在结肠炎大鼠模型和CAC中，DRA表达下调。这表明，改变 在肥胖和结肠癌模型中，氯离子吸收的调节都是一个共同的因素。但是，如果 DRA介导的氯离子吸收的下调可能是发病和 肥胖或结肠炎相关结肠癌的进展尚不清楚。因此，我们假设 肥胖或结肠炎患者结肠中Cl-/HCO3-交换器DRA表达下调增加患结肠的风险 癌症的发生和发展。拟议项目的总体目标是确定 肥胖和结肠炎介导的结肠癌中结肠中氯/HCO3-交换的调节。破译 这将使用Zucker大鼠肥胖和结肠炎相关结肠癌的遗传模型。这些动物 将使用DSS和偶氮甲烷诱导结肠癌的模型来确定功能和 DRA在肥胖和结肠炎相关性结肠癌中调控的分子机制。遵循遗嘱 成为这项提案的具体目标。具体目标1：确定DRA的调节机制 肥胖时的结肠。具体目的2：明确DRA在肥胖介导的结肠癌中的调节作用。 具体目的3：探讨DRA在肥胖性结肠炎中的调节机制。具体目标4： 目的：探讨DRA在结肠炎相关性结肠癌肥胖过程中的调控机制。这 该提案确实将填补对DRA下调监管的理解空白，这可能会起到 在肥胖、肥胖相关结肠癌、结肠炎和CAC的发病机制中起关键作用。成功 作为科布雷协议调查员完成这些研究将提供必要的培训和 生成初步数据，以竞争NIH R01并成为独立调查员。