Behavior and Epigenetic Effects of Chronic Alcohol Exposure in Rats and Human DNA

慢性酒精暴露对大鼠和人类 DNA 的行为和表观遗传影响

• 批准号: 7661798
• 负责人: Vesselin Mitkov Chorbov
• 金额: $ 11.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661798
• 关键词: Adult; Age; Alcohol abuse; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Area; Behavior; Behavior Control; Behavioral; Behavioral Genetics; Blood; Brain; Breeding; Characteristics; Chronic; DNA; DNA Methylation; Data; Dependence; Development; Diet; Epigenetic Process; Ethanol; Etiology; Female; Foundations; Gene Expression; Genes; Genetic; Genome; Goals; Healthcare; Heritability; Human; Interdisciplinary Study; Investigation; Knowledge; Lead; Liquid substance; Liver; Methylation; Organ; Parents; Pathway interactions; Pattern; Predisposition; Preventive Medicine; Promoter Regions; Public Health; Randomized; Rattus; Research; Research Training; Risk; Rodent; Role; Seminal Vesicles; Site; Testing; Testis Brain; Training; Translating; addiction; alcohol abuse prevention; alcohol behavior; alcohol exposure; base; behavior test; epigenetic variation; genome-wide; human DNA; human subject; imprint; male; offspring; problem drinker; programs; promoter; public health relevance; transmission process

DESCRIPTION (provided by applicant): The study of DNA methylation as an important epigenetic pathway may reveal possible effects of alcohol exposure on the alcoholic's DNA methylation profile that probably result in the transmission of altered or imprinted patterns of gene expression to offspring and subsequent predisposition to alcohol related behaviors. The proposed project aims to determine the effects of chronic ethanol exposure on gene methylation patterns, whether changes in DNA methylation are transmitted to offspring and whether such changes correlate with alcoholism related behavioral changes. Behavior of male offspring of chronic ethanol treated and control male rats will be analyzed and high throughput microarrays will be used to identify differentially methylated gene promoter regions within the genome of this offspring. Genes that show differentially methylated patterns between the offspring of ethanol treated and control rats will be analyzed for methylation changes of specific CpG sites in both parents and offspring to analyze heritability. If epigenetic changes precede addiction and confer risk for dependence, that would be a strong argument for causality. These scientific aims are closely coordinated with the training aspects of the project which emphasize development of expertise in rat behavior genetics and epigenetics. Together, the research and training components of the proposed project will provide the applicant with the foundation to pursue research on epigenetic factors and investigate their role in alcohol abuse in human subjects by using animal models. Candidate's long-term goal is to develop a research program that combines rodent and human behavior genetics, including the extent and importance of epigenetic variations and mechanisms by which dynamic and quantitative aspects of alcohol dependent behavior are controlled. PUBLIC HEALTH RELEVANCE: This project is relevant to public health, as new strategies (microarray-based epigenetic profiling followed by specific gene methylation analysis) can be used for testing the epigenetic effects in alcohol behavior in rodents and humans. It will lead to investigations that may advance knowledge in the areas of epigenetics, GxE interaction, treatment, and prevention of alcohol abuse. Health care can then be redirected from curative to individualized preventive medicine based on epigenetic characteristics of one's genetic makeup.

描述（由申请人提供）：DNA甲基化作为一种重要的表观遗传途径的研究可能揭示酒精暴露对酗酒者DNA甲基化谱的可能影响，这可能导致基因表达的改变或印记模式传递给后代，以及随后对酒精相关行为的易感性。该项目旨在确定慢性乙醇暴露对基因甲基化模式的影响，DNA甲基化的变化是否会传递给后代，以及这些变化是否与酒精中毒相关的行为变化相关。将分析慢性乙醇处理的雄性大鼠和对照雄性大鼠的雄性后代的行为，并将使用高通量微阵列来鉴定该后代基因组内的差异甲基化基因启动子区域。将分析在乙醇处理的大鼠和对照大鼠的后代之间显示差异甲基化模式的基因在亲本和后代中的特定CpG位点的甲基化变化，以分析遗传性。如果表观遗传变化先于成瘾并赋予依赖风险，这将是因果关系的有力论据。这些科学目标与该项目的培训方面密切协调，该项目强调发展大鼠行为遗传学和表观遗传学方面的专业知识。拟议项目的研究和培训部分将为申请人提供基础，以进行表观遗传因素的研究，并通过使用动物模型调查其在人类受试者酗酒中的作用。候选人的长期目标是开发一个结合啮齿动物和人类行为遗传学的研究计划，包括表观遗传变异的程度和重要性以及控制酒精依赖行为的动态和定量方面的机制。 公共卫生关系：该项目与公共卫生有关，因为新的策略（基于微阵列的表观遗传分析，然后进行特定基因甲基化分析）可用于测试啮齿动物和人类酒精行为的表观遗传效应。它将导致可能在表观遗传学，GxE相互作用，治疗和预防酒精滥用等领域推进知识的调查。然后，可以根据一个人基因组成的表观遗传特征，将保健从治疗性转向个性化预防性医学。