Project 2 - Genetic analysis of ethanol-related behavior in Drosophila

项目 2 - 果蝇乙醇相关行为的遗传分析

• 批准号: 10429952
• 负责人: MICHAEL S. GROTEWIEL
• 金额: $ 18.99万
• 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/10429952
• 关键词: Alcohol abuse; Bioinformatics; Caenorhabditis elegans; Candidate Disease Gene; Data; Development; Diagnosis; Drosophila genus; Ensure; Ethanol; Etiology; Family; Family member; Gene Family; Genes; Genetic; Grant; Health; Human; Individual; Investigation; Laboratories; Lead; Mediator of activation protein; Modeling; Molecular Genetics; Mus; Neurons; Orthologous Gene; Pathway interactions; Pilot Projects; Publishing; RNA Interference; Rattus; Resistance; Risk; Role; Ryanodine; Ryanodine Receptor Calcium Release Channel; Sedation procedure; Societies; Source; Testing; Transgenes; alcohol abuse therapy; alcohol behavior; alcohol effect; alcohol research; alcohol response; alcohol use disorder; base; behavioral response; drug disposition; fly; gene network; genetic analysis; genetic information; genome wide association study; improved; insight; knock-down; loss of function mutation; member; novel; novel therapeutic intervention; response; success; transcription factor; transcriptomics

Project Summary – Project 2 Alcohol use disorder (AUD) imposes a substantial burden on society with far-reaching health consequences. The identification of novel genes and genetic pathways that influence alcohol-related behaviors will facilitate the development of new therapeutic interventions for AUD. In this project my laboratory will use the Drosophila (fruit fly) model to investigate genes and genetic pathways that have novel influences on ethanol-related behavior. Molecular-genetic information from this project should ultimately lead to better diagnosis, risk determination and treatment of AUD in humans. A major focus for this project will be to explore the role of the MADS-box transcription factor Mef2 family in ethanol-related behavior. Our preliminary studies implicate a MEF2 family member in the subjective response to ethanol (SRE) in humans and also show that the sole fly ortholog Mef2 is required for normal ethanol sedation. Our data suggest that altered ethanol sedation in humans might underlie changes in SRE and that changes in both sedation and SRE might be driven by genetic variance in MEF2 genes. Our results also support the hypothesis that a deeper understanding of the Mef2 family of genes could lead to important insights regarding behavioral responses to ethanol, SRE and potentially AUD. Another major focus of this project will be to continue using the fly as an experimental platform for investigating the role of other candidate genes in ethanol behavior prioritized by our Bioinformatics and Analysis Core and/or implicated by studies in other Center Projects. Given our success with studies on Clic, the ryanodine receptor and Mef2, we will further invest in this cross-species approach for exploring conserved genes and pathways underlying ethanol-related behaviors in flies and multiple aspects of alcohol abuse in humans.

项目摘要 - 项目2 酒精使用障碍（AUD）不可能在深远的健康状态下对社会进行大量烧毁 结果。鉴定新基因和影响与酒精相关行为的遗传途径 将有助于开发AUD的新治疗干预措施。在这个项目中，我的实验室将使用 果蝇（果蝇）模型研究了对基因和具有新影响的基因和遗传途径 与乙醇相关的行为。该项目的分子遗传信息最终应提高更好 人类AUD的诊断，风险确定和治疗。 该项目的主要重点是探索MADS-Box转录因子MEF2家族的角色 与乙醇相关的行为。我们的初步研究暗示了MEF2家庭成员的主观反应 向人类中的乙醇（SRE），也表明正常乙醇需要唯一的苍蝇直系同源物mef2 镇静。我们的数据表明，人类中乙醇镇静的改变可能是SRE的改变，并且 镇静和SRE的变化可能是由MEF2基因的遗传差异驱动的。我们的结果也是如此 支持以下假设，即对MEF2基因家族的更深入了解可能会导致重要 关于对乙醇，SRE和潜在AUD的行为反应的见解。 该项目的另一个主要重点是继续使用Fly作为实验平台 研究其他候选基因在我们的生物信息学和 分析核心和/或由其他中心项目的研究实施。鉴于我们在研究中的研究中取得了成功， Ryanodine接收器和MEF2，我们将进一步投资于这种探索保守的跨物种方法 果蝇中与乙醇相关的行为的基因和途径 人类。