Identification and Characterization of Novel Genetic Mechanisms in Alcohol Use Disorder and Excessive Drinking

项目摘要/摘要 酒精使用障碍(AUD)与个人和社会都付出了巨大的代价。遗传和 环境因素导致AUD和过度饮酒的风险，并更好地了解 特定的风险基因将为预防和治疗提供新的策略。最新的强壮的人类 对AUD和饮酒的全基因组关联研究(GWAS)已经开始发现 新的候选基因。随着越来越多的基因被牵连进来，有必要 研究人员接受了在人类和动物模型研究之间进行研究的培训。这将允许 跨生物体的遗传发现的翻译，用于新基因的后续和表征 机械装置。这项建议涉及对翻译基因研究的两种融合策略的培训 以及过度饮酒。AIM 1将提供培训，以确定来自人类GWAs的基因命中的优先顺序 使用新的突变小鼠品系进行动物研究的后续研究。目标1的目标是从识别 使用小鼠模型对GWAs中的基因进行机械性表征。基于以下原因开发的突变小鼠品系 将通过各种行为分析来评估GWAS的命中率，以确定饮酒行为的哪些方面 都被基因操作改变了；这些研究的最终目标将是开发一种优化的 评估基因对AUD相关行为影响的行为框架。行为分析将包括 急性暴饮式饮酒和饮酒微观结构(在黑暗中饮酒)、升级的衡量标准 依赖后动物的饮酒和戒断(慢性间歇性)的负面情感变化 酒精蒸气暴露模型)，以及对酒精的正面和负面激励作用的敏感性 (酒精对颅内自我刺激的影响)。目标2将利用互补的翻译基因 这种方法寻求利用遗传多样性的小鼠群体来发现基因。具体来说，来自 LGxSM高级交叉线将在一种表型丰富的狂欢类酒精模型上进行测试 饮酒(用吸力计在黑暗中饮酒)以表征消费、血液酒精水平和详细情况 饮酒比赛结构的表征。这项实验的目标是识别与之相关的新基因。 不仅有整体的消费，还有具体的饮酒模式。这一目标将提供 在比赛分析的高级统计方法和数量遗传学技能方面的重要培训 对小鼠GWA来说是必需的。总之，这里提出的研究将产生对 AUD和过度饮酒的遗传学。

Project summary/abstract Alcohol use disorder (AUD) is associated with significant costs to both the individual and society. Genetic and environmental factors contribute to the risk of AUD and excessive drinking, and a better understanding of the specific risk genes will allow for novel strategies for prevention and treatment. Recent well-powered human genome wide association studies (GWAS) of AUD and alcohol consumption have begun to identify multiple novel candidate genes. As increasing numbers of genes are implicated, it will be imperative to have researchers trained to work at the interface between human and animal model research. This will allow for the translation of genetic findings across organisms for follow-up and characterization of novel genetic mechanisms. This proposal involves training in two converging strategies for translational genetic research in AUD and excessive drinking. Aim 1 will provide training in prioritizing genetic hits from human GWAS for follow-up in animal studies using new mutant mouse lines. The goal of Aim 1 is to move from identification of genes in GWAS to mechanistic characterization using mouse models. Mutant mouse lines developed based on GWAS hits will be evaluated on a variety of behavioral assays to identify which aspects of drinking behavior are altered by the genetic manipulation; the ultimate goal of these studies will be to develop an optimized behavioral framework for assessing gene effects on AUD-relevant behaviors. Behavioral assays will include a measure of initiation of acute binge-like drinking and drinking microstructure (Drinking in the Dark), escalation of drinking in post-dependent animals and negative affective changes in withdrawal (chronic intermittent alcohol vapor exposure model), and sensitivity to the positive and negative motivational effects of alcohol (alcohol effects on intracranial self-stimulation). Aim 2 will utilize a complementary translational genetic approach that seeks to discover genes using a genetically diverse mouse population. Specifically, mice from the LGxSM Advanced Intercross Line will be tested on a phenotypically-rich model of binge-like alcohol drinking (Drinking in the dark with lickometers) to characterize consumption, blood alcohol levels, and detailed characterization of drinking bout structure. The goal of this experiment is to identify novel genes associated with not only overall consumption, but also specific aspects of the drinking pattern. This aim will provide significant training in advanced statistical methods for bout analysis and in the quantitative genetics skills needed for mouse GWAS. Together, the studies proposed here will yield critical biological insights into the genetics of AUD and excessive drinking.