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

下调腺瘤（DRA）在肥胖相关结肠炎诱发结肠癌中的调节机制

• 批准号: 10452801
• 负责人: Balasubramanian Palaniappan
• 金额: $ 19.8万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452801
• 关键词: Mechanism; regulation; Down; Regulated; Adenoma

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.

肥胖与结肠癌的风险增加和早期发病有关。大约40%的肥胖相关 癌症发病率在美国记录在案。更具体地说，在西弗吉尼亚州， 与肥胖相关的结肠癌发病率和18%的相关死亡率， 记录在案。类似地，炎症性肠病（IBD）（溃疡性结肠炎（UC）和克罗恩病（Crohn's disease））也可用于治疗炎症性肠病（IBD）。 (CD))已知是结肠癌发展的重要危险因素，即结肠炎相关性 结肠癌（CAC）。CAC之前是临床可检测到的IBD。UC增加CAC风险高达18-20% 而CD在活动性疾病30年后贡献高达8%。它已被证明在结肠在一个 体内遗传性肥胖模型（Zucker大鼠）和体外脂肪细胞来源的分泌组（ADS）模型， 氯离子吸收由Cl-/HCO 3-交换剂介导的肥胖症显著降低。 类似地，在结肠炎大鼠模型和CAC中，p53表达下调。这表明， 氯化物吸收的调节是肥胖和结肠癌模型中的共同因素。但如果 降调节β-内酰胺介导的氯离子吸收可能是导致发病的具体原因， 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-/HCO 3-交换酶的下调会增加结肠炎的风险 癌症发作和进展。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Cl-/HCO 3-交换的调节。破译 为此，将使用肥胖和结肠炎相关结肠癌的Zucker大鼠遗传模型。这些动物 模型将用于用DSS和氧化偶氮甲烷诱导结肠癌，以确定功能和 肥胖症和结肠炎相关结肠癌中β-淀粉样蛋白调节的分子机制。以下人员 这是该提案的具体目标。具体目标1：确定调节胰岛素的机制 肥胖时的结肠具体目标2：确定肥胖介导的结肠癌中的调节。 具体目标3：确定DRA对肥胖期间结肠炎的调节机制。具体目标4： 探讨肥胖时结肠炎相关性结肠癌发生的调控机制。这 该提案确实将解决在理解降调节的缺陷，这可能会发挥 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COBRE雅阁研究者完成这些研究后，将提供必要的培训， 生成初步数据，以竞争NIH R 01并成为独立研究者。