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: 8853213
• 负责人: MICHAEL S. GROTEWIEL
• 金额: $ 25.38万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853213
• 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; mouse model; mutant; nonhuman primate; novel; novel therapeutic intervention; 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（由申请人提供）：与酒精有关的疾病对社会造成了重大负担，并带来了深远的健康后果。鉴定出影响与酒精相关行为的新型基因和遗传途径将有助于开发用于酒精中毒和其他形式的酒精滥用的新治疗干预措施。在这个项目中，我们将研究对乙醇行为影响新颖的基因和遗传途径。该项目的分子遗传信息最终应导致人类中与酒精相关疾病的诊断，风险确定和治疗。 该项目专注于CLIC4/CLIC作为一种新型的小鼠/果蝇基因，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乙醇相关行为 （果蝇）和小鼠，表明它在乙醇作用中具有保守的作用。为了进一步表征CLIC4/CLIC及其在乙醇行为中的相关分子机制，我们在果蝇和小鼠中开发了一项协调的研究。使用果蝇模型，该项目将确定CLIC作用的组织部位（AIM 1），定义CLIC（AI 2）的时间要求（AI 2）和CLIC功能的分子遗传学机制（AIM 3）。使用鼠标模型，该项目将进一步表征大脑中Clic4的乙醇调节（AIM 4A），表征了哺乳动物Clic4在饮酒和其他乙醇行为中的作用（AIM 4B），表征下游分子对Clic4表达改变的分子反应（AIM 4C）（AIM 4C），并研究了clicarear partners cliC4 cliC4的作用（AIM 4C）。 该项目借鉴了PIS Grotewiel（Fly）和Miles（Mouse）指导的两个独立实验室的补充专业知识，并旨在具有几个主要集成点。 CLIC4/CLIC最初通过Miles实验室对基因表达，链接和关联数据进行了一系列分析，将CLIC4/CLIC作为乙醇行为的候选基因。随后，Grotewiel实验室对CLIC进行的遗传分析使CLIC4成为小鼠乙醇行为研究的高优先级（称为初步数据）。这些研究合理地支持对Clic/Clic4如何影响苍蝇（AIM 1和2）和小鼠（AIMS 4A和4B）的乙醇反应的更广泛的研究。此外，现在对小鼠中乙醇响应基因的其他研究（AIMS 4A和4C）正在告知苍蝇中实验的设计，这些实验将研究CLIC作用的机理（AIM 3）。 AIM 3中果蝇研究的结果反过来指导小鼠在哺乳动物乙醇行为中CLIC4的实验设计（AIM 4D）。该项目中有意的跨物种集成在里程和格罗维尔实验室之间的协作框架内实施，将推动对乙醇行为背后的保守机制的遗传研究。