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

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，这种影响可能导致基因表达模式的改变或印记传递给后代，进而导致酒精相关行为的易感。拟议的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遗传给后代，以及这种变化是否与酒精中毒相关的行为改变有关。将分析慢性乙醇处理和对照雄性大鼠的雄性后代的行为，并使用高通量微阵列识别该后代基因组中差异甲基化的基因启动子区域。在乙醇处理的后代和对照大鼠之间显示差异甲基化模式的基因将被分析双亲和后代中特定CpG位点的甲基化变化，以分析遗传力。如果表观遗传变化先于成瘾并赋予依赖风险，那么这将是因果关系的有力论据。这些科学目标与项目的培训方面密切协调，该项目强调老鼠行为遗传学和表观遗传学方面的专业知识的发展。拟议项目的研究和培训部分将共同为申请人提供基础，以进行表观遗传因素的研究，并通过动物模型调查其在人类受试者酒精滥用中的作用。候选人的长期目标是发展一个结合啮齿动物和人类行为遗传学的研究项目，包括表观遗传变异的范围和重要性，以及控制酒精依赖行为的动态和定量方面的机制。

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.