Early binge drinking and gene regulation

早期酗酒与基因调控

• 批准号: 8526297
• 负责人: HOWARD J EDENBERG
• 金额: $ 21.76万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526297
• 关键词: Address; Adult; Affect; Alcohol consumption; Alcoholism; Alcohols; Alleles; Amygdaloid structure; Animal Model; Animals; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood Cells; Brain; Brain region; Calcium Channel; Candidate Disease Gene; Cell Nucleus; Complement; Coupled; DNA; DNA Methylation; Data; Development; Dynorphins; Epidemiology; Ethanol; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genomics; Grant; Heavy Drinking; Human; Individual; Link; Messenger RNA; MicroRNAs; Neurobiology; Nucleus Accumbens; Opioid; Phenotype; Promoter Regions; Protocols documentation; RNA; RNA Splicing; Rattus; Risk Factors; Sampling; Schedule; Sodium Channel; Spliced Genes; System; Testing; Tissues; Ventral Tegmental Area; Work; alcohol effect; alcohol exposure; alcohol response; alcohol use initiation; binge drinking; brain tissue; clinically relevant; drinking; experience; gamma-Aminobutyric Acid; genetics of alcoholism; human tissue; insight; male; neurotransmission; postnatal; preference; research study; transcriptome sequencing

DESCRIPTION (provided by applicant): The overall aim of this new component for INIA is to understand the neurobiology of excessive alcohol consumption. Epidemiological data demonstrate that early initiation of drinking, and particularly excessive drinking, is a major risk factor for eventual alcoholism. Our hypothesis is that both innate differences in gene expression and differences in response to alcohol, particularity to heavy exposure to alcohol in a binge drinking paradigm, contribute to the development of excessive alcohol drinking. We hypothesize that alcohol exposure will affect DNA methylation which will have lasting effects on gene expression and splicing in a way that increases long-term vulnerability to excessive alcohol drinking. All three Specific Aims will be closely linked, by examining gene expression and splicing, DNA methylation, and microRNAs in a coordinated way on the same tissues, so that we can elucidate mechanisms by which alcohol exposure exerts its effects. Our strategy is to study both alcohol-naive animals from lines selected for difference in alcohol preference, to find pre-existing genetic differences that predispose to excessive drinking, and also to study animals that have experienced repeated binge drinking from postnatal day 30 to 58 to determine how that affects gene expression and DNA methylation, and whether the differences persist. We will analyze differences between exposed and unexposed animals at the end of the repeated binges and also 30 days later to see which differences persist. We will focus on key INIA regions: the shell of the nucleus accumbens (Nac-shell), the central nucleus of the amygdala (CeA), and the ventral tegmental area (VTA); we have microarray data from adult males that show many significant differences in gene expression in these regions. Differences found in global studies, and selected candidate genes from human studies, will be tested to determine whether they are controlled in cis. We will study gene expression, splicing, DNA methylation and microRNAs in the same tissues, to allow an integrated, systems-wide understanding of the effects of alcohol that might underlie excessive alcohol consumption. These mechanistic studies cannot be carried out in humans because we can neither control alcohol exposure nor access brain tissue. For that reason, an additional translational component will be to compare the effects of ethanol on key brain regions with those in an accessible tissue, blood, looking forward to potential human studies.

描述（由申请人提供）：INIA的新组成部分的总体目的是了解过度饮酒的神经生物学。流行病学数据表明，早期饮酒，尤其是过量饮酒，是最终酒精中毒的主要危险因素。我们的假设是，基因表达的先天差异和对酒精反应的差异，对暴饮暴食范式中大量暴露于酒精的特殊性，都导致过度饮酒的发展。我们假设酒精暴露会影响DNA甲基化，这将对基因表达产生持久影响，并以增加长期易于饮酒的长期脆弱性的方式。通过在同一组织上以协调的方式检查基因表达和剪接，DNA甲基化和microRNA，这三个特定目标将紧密相连，以便我们可以阐明酒精暴露会产生其作用的机制。我们的策略是从选择的饮酒差异的品系中研究两种饮酒动物，以找到易于饮酒的遗传差异，并研究从第30天到58天经历过狂饮的反复饮酒的动物，以确定如何影响基因表达和DNA甲基化以及差异是否持续存在。我们将分析重复曲折结束时暴露的动物和未暴露的动物之间的差异以及30天后，以查看哪些差异持续存在。我们将重点关注关键INIA区域：伏隔核（NAC-SHELL）的外壳，杏仁核的中央核（CEA）和腹侧侧距区域（VTA）；我们有来自成年男性的微阵列数据，这些数据显示了这些地区的基因表达有许多显着差异。将在全球研究中发现的差异，并将测试人类研究中选定的候选基因，以确定它们是否在顺式中受到控制。我们将研究同一组织中的基因表达，剪接，DNA甲基化和microRNA，以允许对可能过度饮酒的饮酒的影响进行整合，全系统的了解。 这些机械研究不能在人类中进行，因为我们不能控制酒精暴露也无法进入脑组织。因此，另一个翻译成分将是将乙醇对关键大脑区域的影响与可访问的组织，血液，期待潜在的人类研究进行比较。