Epigenetic effects of chronic alcohol consumption on colonic mucosa

长期饮酒对结肠粘膜的表观遗传影响

基本信息

批准号：
7295783
负责人：
SANG WOON CHOI
金额：
$ 18.22万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7295783
关键词：
Address Advocate Affect Aging Alcohol consumption Alcohols Animal Model Biochemical Biological CDKN2A gene Carbon Chemoprevention Chemopreventive Agent Chronic Colon Colorectal Colorectal Cancer Condition DNA DNA Methylation Engineering Environment Epidemiologic Studies Epigenetic Process Equilibrium Folate Gene Expression Genes Genetic Polymorphism Genetically Engineered Mouse Genomics Genotype Genus Cola Goals Heavy Drinking Histones Hyperhomocysteinemia Hypermethylation Individual Investigation Knock-out Laboratories Malignant Neoplasms Mediating Metabolism Methylation Methylenetetrahydrofolate reductase (NADPH)Mucous Membrane Pathway interactions Rectal Cancer Research Research Personnel Research Project Grants Risk Rodent Series Tissues Variant alcohol effect base cancer risk carcinogenesis chronic alcohol ingestion concept experience human study innovation methyl group mouse model novel nucleotide metabolism nutrition programs promoter research study success

项目摘要

DESCRIPTION (provided by applicant): Epidemiologic studies have demonstrated that alcohol consumption enhances colorectal carcinogenesis especially in individuals with folate depletion and/or methylenetetrahydrofolate reductase (MTHFR) homozygous variant genotype, indicating that the co-carcinogenic effect of alcohol is conveyed through the folate mediated one-carbon metabolism, as well as advocating an interaction between alcohol and MTHFR gene, which maintains a balance between biological methylation and nucleotide synthesis. Recently, we identified the fact that chronic alcohol consumption induces hyperhomocysteinemia and genomic DNA hypomethylation in the rodent colon, indicating the potent effects that alcohol exerts on onecarbon metabolism and epigenetic phenomena, and subsequently lending that chronic alcohol consumption modifies critical gene expression through epigenetic changes and provides a co-carcinogenic milieu in the colonic mucosa. Our long-term goal is to find effective strategies for the chemoprevention of alcohol-associated cancer. The studies outlined in this proposal are aimed at defining epigenetic mechanisms by which alcohol consumption affects colorectal carcinogenesis. We therefore hypothesize that chronic alcohol consumption disturbs one-carbon metabolism in the colon and thereby alters epigenetic phenomena including DNA methylation and histone methylation as well as critical gene expression. We further hypothesized that conditions which alter the balance of one-carbon metabolism, such as folate depletion, aging and MTHFR polymorphism, aggravate these epigenetic phenomena induced by chronic alcohol consumption. This application is innovative because two proposed epigenetic phenomena, histone methylation and promoter DNA methylation, have never been explored for the study regarding the alcohol-associated carcinogenesis and the proposed epigenetic interaction between alcohol and MTHFR gene is a new concept that enables individually tailored chemoprevention by genotypes and nutrition status. Based on the results of this application we will apply for a research project grant to finalize the epigenetic effect of chronic alcohol consumption on colorectal carcinogenesis. If those studies can precisely define the epigenetic mechanism for alcohol-associated carcinogenesis, we can develop a new chemopreventive strategy for those cancers.

描述（由申请人提供）：流行病学研究表明，饮酒可以增强结直肠癌的发生，尤其是在叶酸耗尽和/或甲基环甲基二氢叶酸还原酶（MTHFR）纯合变量的基因型中，通过甲基化的饮酒及其相互作用的相互作用，甲基化的疾病及其相互作用，甲基化的疾病及其相互作用，甲基化的疾病是在甲基化的培养基中，甲基化的疾病是繁殖的，这是甲基化的疾病，甲基化的疾病是繁殖的，这是在繁殖中的繁殖，甲基化的态度是繁殖的，这MTHFR基因，该基因在生物甲基化和核苷酸合成之间保持平衡。最近，我们确定了以下事实：慢性酒精消耗诱导啮齿动物结肠中的高体温性结晶性血症和基因组DNA低甲基化，表明酒精对Onecarbon代谢和表观遗传现象的有效作用，并随后通过epeconic sige-coreonic进行了co-carc，并促进了cor的表达。粘膜。我们的长期目标是寻找与酒精相关癌症化学预防的有效策略。该提案中概述的研究旨在定义饮酒会影响大肠癌发生的表观遗传机制。因此，我们假设慢性酒精消耗干扰了结肠中的单碳代谢，从而改变了包括DNA甲基化和组蛋白甲基化以及关键基因表达在内的表观遗传现象。我们进一步假设，改变一碳代谢的平衡的条件，例如叶酸耗竭，衰老和MTHFR 多态性，加剧了由慢性酒精消耗引起的这些表观遗传现象。该应用具有创新性，因为从未探索过两种提出的表观遗传现象，组蛋白甲基化和启动子DNA甲基化，从未探索过有关酒精相关的致癌作用以及酒精和MTHFR基因之间提出的表观遗传学相互作用的研究，是一个新的概念，可以单独通过Genotypes和Lunretition Chate and Chemoption和Lutretition ChemitiTy Chemoptial量身定制化学量。根据本应用的结果，我们将申请研究项目赠款，以最终确定长期饮酒对结直肠癌发生的表观遗传作用。如果这些研究可以精确定义与酒精相关的癌变的表观遗传机制，那么我们可以为这些癌症制定新的化学预防策略。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification.

DOI：
10.1002/ijc.24003
发表时间：
2009-05-01
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Sohn, Kyoung-Jin;Jang, Hyeran;Campan, Mihaela;Weisenberger, Daniel J.;Dickhout, Jeffrey;Wang, Yi-Cheng;Cho, Robert C.;Yates, Zoe;Lucock, Mark;Chiang, En-Pei;Austin, Richard C.;Choi, Sang-Woon;Laird, Peter W.;Kim, Young-In
通讯作者：
Kim, Young-In

DNA methylation, an epigenetic mechanism connecting folate to healthy embryonic development and aging.