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

项目摘要-项目2 酒精使用障碍(AUD)给社会带来了沉重的负担，对健康有着深远的影响 后果。影响酒精相关行为的新基因和遗传途径的发现 将促进开发新的澳门氏症治疗干预措施。在这个项目中，我的实验室将使用 果蝇(果蝇)模型研究对果蝇有新影响的基因和遗传途径 与酒精有关的行为。来自这个项目的分子遗传学信息最终应该会带来更好的 人类AUD的诊断、风险确定和治疗。 该项目的一个主要焦点将是探索MADS-box转录因子Mef2家族在 与酒精有关的行为。我们的初步研究表明MEF2家族的一名成员参与了主观反应 人类对乙醇(SRE)的敏感性，并表明正常乙醇需要唯一的果蝇直系基因MEF2 镇静剂。我们的数据表明，人类改变的酒精镇静可能是SRE变化的基础，而且 镇静和SRE的变化可能是由MEF2基因的遗传变异驱动的。我们的结果也是 支持这样一种假设，即对MEF2基因家族的深入了解可以导致重要的 对酒精、SRE和潜在的AUD的行为反应的见解。 该项目的另一个主要关注点是继续使用Fly作为实验平台 研究其他候选基因在酒精行为中的作用，这是我们的生物信息学和 分析核心和/或受其他中心项目研究的影响。鉴于我们对CLIC的研究取得了成功， Ryanodine受体和Mef2，我们将进一步投资于这种跨物种的方法来探索保守的 果蝇酒精相关行为的基因和途径以及酒精滥用的多个方面 人类。

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.