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

描述(申请人提供)：将DNA甲基化作为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甲基化特征的可能影响，这些影响可能导致基因表达的改变或印记模式传递给后代，以及随后的酒精相关行为的易感性。这项拟议的项目旨在确定慢性酒精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，以及这种变化是否与酒精中毒相关的行为变化相关。将分析慢性酒精处理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识别这些后代基因组中差异甲基化的基因启动子区域。酒精处理组和对照组大鼠的后代之间表现出不同甲基化模式的基因将被分析父母和后代中特定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带来依赖风险，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门知识。总之，拟议项目的研究和培训部分将为申请者提供基础，以便继续研究表观遗传因素，并通过动物模型调查它们在人类受试者酗酒中的作用。侯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。 公共卫生相关性：该项目与公共卫生相关，因为可以使用新的策略(基于微阵列的表观遗传学图谱，然后进行特定的基因甲基化分析)来测试啮齿动物和人类酒精行为的表观遗传学效应。它将导致可能促进表观遗传学、GxE相互作用、治疗和预防酒精滥用领域的知识的调查。然后，医疗保健可以根据一个人的基因构成的表观遗传特征，从治疗性转向个性化的预防医学。

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.