Cross-species genetic analysis of ethanol-related behavior

乙醇相关行为的跨物种遗传分析

• 批准号: 9069363
• 负责人: MICHAEL S. GROTEWIEL
• 金额: $ 26.16万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069363
• 关键词: Acute; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol-Related Disorders; Alcoholism; Behavior; Behavioral; Bioinformatics; Biological Models; Brain; Candidate Disease Gene; Chronic; Collaborations; Data; Development; Diagnosis; Dose; Drosophila genus; Ethanol; Exhibits; Gene Delivery; Gene Expression; Genes; Genetic; Genetic Models; Goals; Health; Human; Individual; Invertebrates; Investigation; Laboratories; Laboratory mice; Lead; Mediating; Meta-Analysis; Modeling; Molecular; Molecular Genetics; Mus; Nervous system structure; Neurons; Outcome; Pathway interactions; Physiological; Play; Prefrontal Cortex; Publishing; RNA Interference; Regulation; Risk; Role; Series; Signal Pathway; Site; Societies; Tissues; Vertebrates; Viral Vector; Work; alcohol behavior; alcohol content; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; alcoholism therapy; behavioral outcome; behavioral response; behavioral study; design; drinking; drinking behavior; fly; follow-up; genetic analysis; genetic information; knock-down; mouse model; mutant; nonhuman primate; novel; novel therapeutic intervention; overexpression; research study; response; sedative

DESCRIPTION (provided by applicant): Alcohol-related disorders impose 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 alcoholism and other forms of alcohol abuse. In this project we will investigate genes and genetic pathways that have novel influences on ethanol behavior. Molecular-genetic information from this project should ultimately lead to better diagnosis, risk determination and treatment of alcohol-related disorders in humans. This project focuses on Clic4/Clic as a novel mouse/Drosophila gene that affects behavioral responses to ethanol. Preliminary studies indicate that this gene influences ethanol-related behavior in both fruit flies (Drosophila) and mice, suggesting that it has a conserved role in ethanol action. To further characterize Clic4/Clic and its associated molecular mechanisms in ethanol behavior, we have developed a coordinated study in Drosophila and mice. Using the Drosophila model, this project will identify the tissue site of Clic action (Aim 1), define the temporal requirements for Clic (Ai 2) and delineate molecular-genetic mechanisms of Clic function (Aim 3). Using the mouse model, this project will further characterize ethanol regulation of Clic4 in the brain (Aim 4A), characterize the role of mammalian Clic4 in drinking and other ethanol behaviors (Aim 4B), characterize downstream molecular responses to altered Clic4 expression (Aim 4C), and investigate the role of a focused set of molecular partners implicated in Clic4 action (Aim 4D). This project draws on the complementary expertise of two independent laboratories directed by PIs Grotewiel (fly) and Miles (mouse) and is designed to have several major points of integration. Clic4/Clic was originally implicated as a candidate gene for ethanol behavior by a series of analyses by the Miles laboratory on gene expression, linkage and association data. Subsequent genetic analysis of Clic in the fly by the Grotewiel laboratory made Clic4 a high priority locus for ethanol behavioral studies in the mouse (described as preliminary data). These studies come together to rationally support a more extensive investigation of how Clic/Clic4 influences ethanol responses in flies (Aims 1 and 2) and mice (Aims 4A and 4B). Furthermore, additional studies on ethanol-responsive genes in the mouse (Aims 4A and 4C) are now informing the design of experiments in flies that will investigate mechanisms of Clic action (Aim 3). The results of the Drosophila studies in Aim 3 will in turn guide the design of experiments in mice on mechanisms for Clic4 in mammalian ethanol behavior (Aim 4D). The deliberate cross-species integration in this project, implemented within a collaborative framework between the Miles and Grotewiel laboratories, will drive a vigorous genetic investigation of conserved mechanisms underlying ethanol behavior.

描述(申请人提供)：与酒精相关的障碍给社会带来了巨大的负担，对健康造成了深远的影响。识别影响酒精相关行为的新基因和遗传途径将有助于开发针对酒精中毒和其他形式的酒精滥用的新的治疗干预措施。在这个项目中，我们将研究对酒精行为有新影响的基因和遗传途径。来自该项目的分子遗传学信息最终将导致对人类酒精相关疾病的更好诊断、风险确定和治疗。本项目的重点是Clic4/Clic，这是一种新的小鼠/果蝇基因，可以影响对乙醇的行为反应。初步研究表明，该基因影响两种果蝇的酒精相关行为。 (果蝇)和小鼠，这表明它在乙醇作用中具有保守的作用。为了进一步研究Clic4/ClIC及其在乙醇行为中的相关分子机制，我们在果蝇和小鼠身上开展了一项协同研究。利用果蝇模型，该项目将确定CLIC作用的组织部位(目标1)，定义CLIC的时间需求(Ai 2)，并描绘CLIC功能的分子遗传学机制(目标3)。利用小鼠模型，该项目将进一步表征大脑中Clic4对乙醇的调节(Aim 4A)，表征哺乳动物Clic4在饮酒和其他乙醇行为中的作用(Aim 4B)，表征下游对Clic4表达变化的分子反应(Aim 4C)，并研究与Clic4作用有关的一组重点分子伙伴的作用(Aim 4D)。该项目利用了由PIS Grotewiel(Fly)和Miles(MICE)指导的两个独立实验室的互补专业知识，并设计有几个主要的集成点。通过迈尔斯实验室对基因表达、连锁和关联数据的一系列分析，Clic4/Clic最初被认为是酒精行为的候选基因。Grotewiel实验室随后对苍蝇中的ClC进行了遗传分析，使Clic4成为小鼠酒精行为研究的高优先级基因座(描述为初步数据)。这些研究结合在一起，合理地支持了一项更广泛的研究，即Clic/Clic4如何影响苍蝇(目标1和2)和小鼠(目标4A和4B)的乙醇反应。此外，对小鼠酒精反应基因的更多研究(目标4A和4C)现在正在为苍蝇实验的设计提供信息，这些实验将研究CLIC的作用机制(目标3)。在Aim 3中对果蝇的研究结果将反过来指导小鼠关于Clic4在哺乳动物酒精行为中的机制的实验设计(Aim 4D)。在迈尔斯实验室和格罗特维尔实验室之间的合作框架内，这个项目中刻意的跨物种整合将推动对乙醇行为背后保守机制的强有力的遗传研究。

项目成果

Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease.

• DOI: 10.1242/bio.20147559
• 发表时间: 2014-04-04
• 期刊: Biology open
• 影响因子: 2.4
• 作者: Jones MA;Amr S;Ferebee A;Huynh P;Rosenfeld JA;Miles MF;Davies AG;Korey CA;Warrick JM;Shiang R;Elsea SH;Girirajan S;Grotewiel M
• 通讯作者: Grotewiel M