Obesity-Related Insulin Resistance Signaling Pathway Factors and Colon Cancer

肥胖相关的胰岛素抵抗信号通路因素与结肠癌

基本信息

批准号：
8112436
负责人：
Li Li
金额：
$ 47.27万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8112436
关键词：
1-Phosphatidylinositol 3-Kinase 5&apos -AMP-activated protein kinase AKT1 gene AKT2 gene AKT3 gene Address Adult Affect Age BRAF gene Biological Biological Models Body Weight Changes Body mass index Candidate Disease Gene Case-Control Studies Colon Carcinoma Complex DNA Data Development Epidemic Epidemiologic Studies FOXO1A gene FOXO3A gene Family Gender Genes Genetic Genetic Polymorphism Genetic Variation Goals Growth Factor Haplotypes Health Homeostasis IGF1R gene IRS1 gene IRS2 gene Insulin Insulin Resistance Insulin Signaling Pathway Joints Link MAP2K1 gene MAPK1 gene MAPK3 gene MDM2 gene Measures Mediating Metabolic Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Modeling NF-kappa B Obesity PDPK1 gene PI3K/AKT PIK3CA gene PIK3CB gene PIK3CG gene PIK3R3 gene PTEN gene PTPN11 gene Pathway Analysis Pathway interactions Peroxisome Proliferator-Activated Receptors Play Population Population Control Population Study Proto-Oncogene Proteins c-akt Raptors Ras/Raf Recruitment Activity Research Priority Risk Role SHC1 gene STK11 gene Sampling Signal Pathway Signal Transduction Somatomedins TNFRSF5 gene TSC1 gene TSC2 gene Variant Weight Gain Woman Work cancer risk colon carcinogenesis epidemiologic data insulin-related factor mTOR protein men novel p65 population based public health priorities

项目摘要

DESCRIPTION (provided by applicant): Obesity is now established as a potential cause for colon cancer. While the underlying mechanisms mediating the obesity-colon cancer link are not well understood, increasing evidence supports that Insulin resistance resulting from long-term energy imbalance and subsequent perturbation of metabolic homeostasis and insulin signaling pathways form the core of obesity-related colon carcinogenesis. Genetic variations within genes in key insulin and growth factor signaling pathways may, or in combination with obesity, drive the development of colon cancer, but have been little studied. The fact that obesity is escalating as an epidemic worldwide makes the exploration of the mechanistic connections between obesity and colon cancer a pressing public health and research priority. Therefore, we propose a genetic epidemiologic study of the relation of colon cancer with obesity and candidate genes in four critical insulin and related growth factor signaling pathways: 1) phosphatidylinositol-3 Kinase/protein kinase B (PI3K/AKT) signaling cascade; 2) AMP-activated protein kinase (AMPK) pathway; 3) mitogen-activated protein (MAP) kinase pathway; and 4) peroxisome proliferators-activated receptors (PPARs). Each of these pathways plays an important role linking increased adiposity to colon carcinogenesis and model systems indicate that crosstalk occurs among them. We will use both conventional statistical approaches and a novel hierarchical model to comprehensively evaluate obesity and adult weight gain, candidate gene polymorphisms and haplotypes, and their potential joint and interactive effects on colon cancer. The unifying theme of this proposal is that obesity and candidate gene variants within these pathways may act alone or jointly to drive colon carcinogenesis. This study builds upon an ongoing population-based case-control study where epidemiologic data and DNA samples from 1,250 incident colon cancer cases and 1,500 population controls has already being collected. This relatively large study population will be readily available and allow us to dissect complex gene-gene and gene-obesity interactions to gain in- depth understanding of mechanistic link between obesity and colon carcinogenesis. PUBLIC HEALTH RELEVANCE: This study builds upon an ongoing population-based case-control study where epidemiologic data and DNA samples from 1,250 incident colon cancer cases and 1,500 population controls have already being collected. This relatively large study population will be readily available and allow us to dissect complex gene-gene and gene-obesity interactions to gain in-depth understanding of mechanistic link between obesity and colon carcinogenesis.

描述（由申请人提供）：现在将肥胖症确定为结肠癌的潜在原因。虽然介导肥胖 - 可癌连接的基本机制尚不清楚，但越来越多的证据支持表明，长期能量失衡以及随后的代谢稳态和胰岛素信号途径的扰动引起的胰岛素抵抗，构成了肥胖相关结肠癌的核心。关键胰岛素和生长因子信号传导途径中基因内的遗传变异可能或与肥胖相结合，促进结肠癌的发展，但很少研究。在全球流行病中，肥胖症正在升级，这一事实使人们对肥胖症与结肠癌之间的机械联系成为公共卫生和研究的重中之重。因此，我们提出了四个关键胰岛素和相关生长因子信号传导途径中结肠癌与肥胖和候选基因之间关系的遗传流行病学研究：1）磷脂酰肌醇-3激酶/蛋白激酶/蛋白激酶B（PI3K/AKT）信号传导级联； 2）AMP激活的蛋白激酶（AMPK）途径； 3）有丝分裂原激活的蛋白（MAP）激酶途径； 4）过氧化物酶体增殖物激活受体（PPARS）。这些途径中的每一个都起着重要的作用，将增加的肥胖与结肠癌的发生联系起来，模型系统表明串扰发生在其中。我们将同时使用常规统计方法和新型的分层模型来全面评估肥胖和成人体重增加，候选基因多态性和单倍型，以及它们对结肠癌的潜在关节和交互作用。该提案的统一主题是，这些途径中的肥胖和候选基因变体可能单独或共同起作用结肠癌。这项研究基于一项正在进行的基于人群的病例对照研究，其中已经收集了1,250例入射结肠癌病例的流行病学数据和DNA样本，并且已经收集了1,500个人群对照。这个相对较大的研究人群将很容易获得，并使我们能够剖析复杂的基因基因和基因 - 肥胖相互作用，从而深入了解肥胖与结肠癌之间的机械联系。公共卫生相关性：这项研究基于一项正在进行的基于人群的病例对照研究，其中已经收集了来自1,250例事件的结肠癌病例和1,500个人口对照的流行病学数据和DNA样本。这个相对较大的研究人群将很容易获得，并使我们能够剖析复杂的基因基因和基因 - 肥胖相互作用，以深入了解肥胖与结肠癌之间的机械联系。