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

乙醇相关行为基因网络的跨物种研究

• 批准号: 10429945
• 负责人: MICHAEL F MILES
• 金额: $ 155.77万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429945
• 关键词: Affect; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Area; Behavior; Behavioral; Bioinformatics; Brain; CRISPR/Cas technology; Caenorhabditis elegans; Candidate Disease Gene; Communities; Consumption; Cre-LoxP; DNA Microarray Chip; Data; Dependence; Development; Disease; Drosophila genus; Environmental Risk Factor; Ethanol; Ethanol Metabolism; Etiology; Event; Expression Profiling; Funding; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Variation; Genetic Vectors; Genetic study; Genomic approach; Genomics; Grant; Human; Human Genetics; Individual; Intervention; Invertebrates; Investigation; Lead; Measures; Meta-Analysis; Modernization; Molecular; Mus; Pattern; Phase; Phenotype; Pilot Projects; Positioning Attribute; Predisposition; Prevention; Public Health; RNA Interference; Rattus; Regulation; Reporting; Research; Research Personnel; Research Project Grants; Resources; Risk; Rodent; Role; Sampling; Sampling Studies; Scheme; Statistical Data Interpretation; Statistical Methods; Structure; Substance abuse problem; Sum; Testing; Therapeutic; Validation; Variant; Viral Vector; Work; alcohol behavior; alcohol research; alcohol response; alcohol use disorder; analysis pipeline; behavioral genomics; behavioral phenotyping; comorbidity; data sharing; design; exome sequencing; fly; gene discovery; gene network; genetic approach; genetic risk factor; genetic variant; genome wide association study; genome-wide; genome-wide analysis; genomic data; human model; innovation; interest; next generation sequencing; novel; novel diagnostics; overexpression; programs; risk variant; success; trait; transcriptome sequencing; validation studies

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.

项目总结 – 总体 酒精使用障碍（AUD）是一个主要的公共健康负担。 对澳元的敏感性至关重要，并且可能是多种变体的结果，每种变体对风险的影响都较小。 迄今为止，动物模型和人类的基因研究在识别个体方面进展缓慢 然而，现代高通量方法，例如全基因组关联研究。 或基因组表达谱有望快速增加潜在候选影响基因库 该 P50 酒精研究中心提案提出了新颖且高度集成的整体设计。 专注于 AUD 遗传学的基因发现和功能解释。 更新我们目前资助的 P50，该 P50 支持 VCU 酒精研究中心 (VCU-ARC)，该中心 2009 年首次获得 P20 发展中心拨款资助。我们在过去取得了重大进展 4.5 年，在此寻求既继续我们先前方向的各个方面，又将我们的工作扩展到新的领域 地区。 由于三个新特点，我们的方法仍然具有创新性和重要意义：1）关注基因 促成 AUD 相关表型和乙醇行为的网络，而不是单个基因；2）交叉 物种遗传和基因组学分析，以验证候选基因并影响网络乙醇行为； 3）高度集成的中心设计，通过跨物种的跨项目快速共享数据 分析管道提供排序的基因列表或网络，以便在组件中进行进一步的实验验证 我们请求为五个研究项目提供五年的支持，并为基因研究提供试点资助。 蠕虫、苍蝇、小鼠、大鼠和人类将代表新的研究领域，另外两个项目将代表新的研究领域。 更新当前项目的总体战略，但将进行两个新的研究领域。 人类遗传学采用最先进的统计方法来利用大型全基因组的力量 对与 AUD 显着相关的表型进行关联和外显子组测序研究。 由管理核心、生物信息学和分析核心以及啮齿动物行为核心提供支持。 这些项目和核心中提出的科学工作显然大于其各个部分的总和，因为 VCU-ARC 组件的高度交互结构 VCU-ARC 非常适合成为一个 国家资源，为增进我们对病因学的理解做出了重大贡献 AUD 及其预防和治疗。