Cross-Species Investigation of Gene Networks for Ethanol-Related Behaviors

描述（由申请人提供）：酒精使用障碍（AUDs）是一种主要的公共卫生负担。遗传风险因素对AUDs的易感性起着至关重要的作用，可能是许多变异的结果，每种变异对风险的贡献都不大。迄今为止，在动物模型和人类中进行的遗传研究在识别基因个体风险变异方面进展缓慢。然而，现代高通量方法，如全基因组关联研究或基因组表达谱，有望迅速增加影响AUDs的潜在候选基因池。P50酒精研究中心的提议提出了一个新颖的、高度集成的整体设计，专注于AUDs的基因发现和功能解释。这项申请是P20发展中心赠款的产物，该赠款于2009年建立了VCU酒精研究中心。在取得了重大进展之后，我们在此建议扩展和扩大该中心。我们的方法包括三个新特点：1)专注于促进aud相关表型的基因网络，而不是单一基因；2)跨物种遗传和基因组学分析，验证影响乙醇行为的候选基因和网络；3)高度整合的中心设计，通过跨物种分析管道在项目间快速共享数据，为组件项目的进一步实验验证提供排序基因列表或网络。我们要求5年支持6个研究项目，并为小鼠、蠕虫、苍蝇和人类的基因研究提供试点资助。人类遗传学方面将有三个项目，其中包括一个新的临床实验室组成部分，用于在受控环境中评估人类对乙醇行为反应的目标遗传影响。所有项目将由行政核心，分析和信息学核心和啮齿动物行为核心的支持。由于VCU-ARC组件的高度交互结构，这些项目和核心中提出的科学工作显然大于其部分的总和。VCU-ARC将成为一项全国性资源，为提高我们对AUDs病因及其预防和治疗的理解做出重大贡献。

DESCRIPTION (provided by applicant): Alcohol use disorders (AUDs) represent a major public health burden. Genetic risk factors contribute critically to susceptibility to AUDs likely a result of many variants each contributing modestly to risk. Genetic studies in animal models and humans have to date made slow progress in identifying genes individual risk variants. However, modern high-throughput approaches such as genome-wide association studies or genomic expression profiling promise to rapidly increase the pool of potential candidate genes influencing AUDs. This proposal for a P50 Alcohol Research Center presents a novel and highly integrated overall design to focus on both gene discovery and functional interpretation for the genetics of AUDs. This application is the outgrowth of a P20 Developmental Center grant that established the VCU Alcohol Research Center in 2009. Having made significant progress, we propose here to extend and enlarge that Center. Our approach includes three novel features: 1) A focus on gene networks contributing to AUD-related phenotypes, rather than single genes; 2) A cross-species genetic and genomics analysis to validate candidate genes and networks affecting ethanol behaviors; 3) A highly integrative Center design with rapid data sharing across projects through a cross-species analysis pipeline to provide ranked gene lists or networks for further experimental validation in the component projects. We request five years of support for six research projects and pilot grants for genetic studies in mice, worms, flies, and humans. Three projects will be in human genetics with a novel clinical laboratory component for assessing targeted genetic influences on human behavioral responses to ethanol in a controlled environment. All projects will be supported by an Administrative Core, an Analytic and Informatics Core and a Rodent Behavioral Core. The scientific work proposed in these projects and cores are clearly greater than the sum of their parts, due to the highly interactive structure of the VCU-ARC components. The VCU-ARC is well positioned to become a national resource making major contributions to the advancement of our understanding of the etiology of AUDs and their prevention and treatment.