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

项目概要/摘要 酒精使用障碍（AUD）与个人和社会的重大成本有关。遗传和 环境因素会增加AUD和过量饮酒的风险，更好地了解 特定的风险基因将允许新的预防和治疗策略。最近， AUD和酒精消费的全基因组关联研究（GWAS）已经开始确定多个 新的候选基因随着越来越多的基因受到牵连， 研究人员接受培训，从事人类和动物模型研究之间的接口工作。这将允许 跨生物体的遗传发现翻译，以跟踪和表征新的遗传发现， 机制等这项建议涉及两个融合战略的翻译遗传学研究的培训， 澳元和过度饮酒。Aim 1将提供优先考虑人类GWAS遗传命中的培训， 使用新的突变小鼠品系进行动物研究的后续研究。目标1的目标是从确定 使用小鼠模型对GWAS中的基因进行机械表征。突变小鼠品系的开发基于 将通过各种行为分析来评估GWAS点击率，以确定饮酒行为的哪些方面 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 急性暴饮暴食样饮酒和饮酒微观结构（黑暗中饮酒）开始的测量，升级 饮酒后依赖的动物和消极的情感变化，在撤退（慢性间歇性 酒精蒸汽暴露模型），以及对酒精的积极和消极激励作用的敏感性 （酒精对颅内自我刺激的影响）。目的2将利用互补的翻译基因 这种方法试图利用遗传多样性的小鼠群体来发现基因。具体来说，来自 LGxSM高级杂交系将在一个表型丰富的酗酒模型上进行测试 饮酒（在黑暗中用Lickometers饮酒），以表征消费，血液酒精水平和详细的 饮用结构的表征。本实验的目的是鉴定与此相关的新基因。 不仅与总体消费有关，还与饮酒模式的特定方面有关。这一目标将提供 在布特分析的先进统计方法和数量遗传学技能方面的重要培训 需要小鼠GWAS。总之，这里提出的研究将产生关键的生物学见解， 遗传学的AUD和过度饮酒。

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.