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

基本信息

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
项目类别：
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&apos 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

项目摘要

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发有关，大约 40% 的肥胖与肥胖有关。更具体地说，美国的癌症发病率高达 49%。与肥胖相关的结肠癌发病率和 18% 的相关死亡率同样，炎症性肠病（IBD）（溃疡性结肠炎（UC）和克罗恩病）也有记录。 (CD))已知是结肠癌发生的重要危险因素，即结肠炎相关性结肠癌 (CAC) 之前出现临床可检测的 IBD，可使 CAC 风险增加 18-20%。而 CD 在活动性疾病 30 年后贡献高达 8%，这已在结肠中得到证实。体内遗传性肥胖模型（Zucker 大鼠）和体外脂肪细胞衍生分泌组（ADS）模型肥胖表明Cl-/HCO3-交换剂DRA介导的氯离子吸收显着降低。类似地，在结肠炎和 CAC 大鼠模型中，DRA 下调，这表明 DRA 的改变。氯化物吸收的调节是肥胖和结肠癌模型中的共同因素。 DRA 介导的氯离子吸收的下调可能是导致这种现象发生和发生的具体原因。肥胖或结肠炎相关结肠癌的进展尚不清楚，因此，我们发现。肥胖或结肠炎患者结肠中 Cl-/HCO3- 交换剂 DRA 下调会增加结肠癌风险该项目的总体目标是确定癌症的发生和进展的机制。肥胖和结肠炎介导的结肠癌中结肠中 Cl-/HCO3- 交换的调节。为此，将使用肥胖和结肠炎相关结肠癌的 Zucker 大鼠遗传模型。模型将用于通过 DSS 和氧化偶氮甲烷诱导结肠癌，以确定其功能和功能。以下将探讨 DRA 在肥胖和结肠炎相关结肠癌中调节的分子机制。是本提案的具体目标具体目标 1：确定 DRA 的监管机制。具体目标 2：明确 DRA 在肥胖介导的结肠癌中的调节作用。具体目标 3：确定肥胖期间 DRA 调节结肠炎的机制。描述肥胖期间结肠炎相关结肠癌中 DRA 的调节机制。该提案确实将解决对 DRA 下调的理解上的空白，这可能会起到一定的作用在肥胖、肥胖相关结肠癌、结肠炎和 CAC 的发病机制中发挥着关键作用。作为 COBRE ACCORD 研究者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 并成为独立研究者。