Cross-species investigation of gene networks for ethanol-related behaviors

项目摘要--总体 酒精使用障碍(AUD)是一个主要的公共卫生负担。遗传风险因素导致 对AUDS的易感性至关重要，很可能是许多变种的结果，每个变种都略微增加了风险。 到目前为止，动物模型和人类的遗传学研究在识别个体方面进展缓慢。 遗传风险变种。然而，现代的高通量方法，如全基因组关联研究 或基因组表达谱有望迅速增加潜在候选基因库，影响 AUDS。这份关于P50酒精研究中心的提案提出了一个新颖的、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。此应用程序是一个 更新我们目前资助的P50，以支持VCU酒精研究中心(VCU-ARC)，该中心是 2009年首次由P20发展中心赠款资助。在过去的几年里，我们取得了重大进展 4.5年来，我们在这里寻求既延续我们先前方向的各个方面，又将我们的工作扩展到新的 区域。 我们的方法仍然是创新和重要的，因为有三个新的特点：1)关注基因 有助于AUD相关表型和酒精行为的网络，而不是单基因；2)杂交- 物种遗传和基因组分析，以验证影响酒精行为的候选基因和网络； 以及3)高度集成的中心设计，通过跨物种实现跨项目的快速数据共享 分析流水线，提供已排序的基因列表或网络，用于在组件中进行进一步的实验验证 项目。我们要求为五个研究项目提供五年的支持，并为#年的基因研究提供试点资助。 蠕虫、苍蝇、老鼠、老鼠和人类。三个项目将代表新的研究领域，另外两个项目将 更新他们当前项目的总体战略，但要有新的调查领域。将有两个项目进入 人类遗传学与最先进的统计方法，以利用大基因组范围的力量 与AUDS显著相关的表型的关联和外显子组测序研究。所有项目都将 由一个行政核心、一个生物信息学和分析核心以及一个啮齿动物行为核心提供支助。 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，因为 VCU-ARC组件的高度交互结构。VCU-ARC处于有利地位，有望成为 国家资源，为促进我们对该病病因的理解做出了重大贡献 AUDS及其随后的预防和治疗。

Project Summary – Overall Alcohol use disorders (AUDs) represent a major public health burden. Genetic risk factors contribute critically to susceptibility to AUDs and are 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 individual genetic 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 a renewal of our currently funded P50 that supports the VCU Alcohol Research Center (VCU-ARC), which was first funded with a P20 Developmental Center grant in 2009. We have made significant progress over the past 4.5 years and here seek to both continue aspects of our prior directions but also to extend our work into new areas. Our approach continues to be innovative and significant due to three novel features: 1) A focus on gene networks contributing to AUD-related phenotypes and ethanol behaviors, rather than single genes; 2) A cross- species genetic and genomics analysis to validate candidate genes and networks affecting ethanol behaviors; and 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 five research projects and pilot grants for genetic studies in worms, flies, mice, rats and humans. Three projects will represent new areas of study, while two others will renew their overall strategy of current projects but with novel areas of investigation. Two projects will be in human genetics with state-of-the-art statistical approaches to leverage the power of large genome-wide association and exome sequencing studies on phenotypes significantly associated with AUDs. All projects will be supported by an Administrative Core, a Bioinformatics and Analysis Core and a Rodent Behavioral Core. The scientific work proposed in these projects and cores is clearly greater than the sum of its 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 subsequently their prevention and treatment.