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

描述(由申请人提供)：酒精使用障碍(AUD)是一个主要的公共卫生负担。遗传风险因素是AUDS易感性的关键因素，可能是由于许多变异造成的，每个变异对风险的贡献都不大。到目前为止，在动物模型和人类中进行的遗传学研究在识别单个风险变量的基因方面进展缓慢。然而，现代的高通量方法，如全基因组关联研究或基因组表达谱分析，有望迅速增加影响AUD的潜在候选基因库。这份关于P50酒精研究中心的提案提出了一种新颖且高度集成的总体设计，专注于AUDS遗传学的基因发现和功能解释。这项申请是P20发展中心拨款的产物，该基金于2009年成立了VCU酒精研究中心。在取得重大进展后，我们在此提议扩大和扩大该中心。我们的方法包括三个新功能：1)专注于促进AUD相关表型的基因网络，而不是单个基因；2)跨物种遗传和基因组分析，以验证影响乙醇行为的候选基因和网络；3)高度集成的中心设计，通过跨物种分析管道在项目之间快速共享数据，为组成部分项目的进一步实验验证提供排序的基因列表或网络。我们要求为六个研究项目提供五年的支持，并为老鼠、蠕虫、苍蝇和人类的基因研究提供试点资助。三个项目将在人类遗传学领域进行，其中包括一个新的临床实验室组成部分，用于评估受控环境中有针对性的基因对人类对乙醇的行为反应的影响。所有项目都将得到一个行政核心、一个分析和信息学核心以及一个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各部分的总和。VCU-ARC处于有利地位，将成为一个国家资源，为促进我们对AUDS的病因及其预防和治疗的了解做出重大贡献。

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.