Cross-species genetic analysis of ethanol-related behavior

描述（由申请人提供）：酒精相关疾病给社会带来了巨大的负担，并对健康产生了深远的影响。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有新影响的基因和遗传途径。该项目的分子遗传信息最终将导致更好的诊断，风险确定和治疗人类酒精相关疾病。 该项目的重点是Clic4/Clic作为一种新的小鼠/果蝇基因，影响乙醇的行为反应。初步研究表明，这种基因影响了果蝇与乙醇相关的行为 （果蝇）和小鼠，这表明它在乙醇作用中具有保守作用。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展了一项协调研究。使用果蝇模型，该项目将确定组织位点的Clic行动（目标1），定义的时间要求的Clic（Ai 2）和描绘的分子遗传机制的Clic功能（目标3）。使用小鼠模型，该项目将进一步表征Clic 4在大脑中的乙醇调节（Aim 4A），表征哺乳动物Clic 4在饮酒和其他乙醇行为中的作用（Aim 4B），表征下游分子对Clic 4表达改变的反应（Aim 4C），并研究一组与Clic 4作用有关的分子伴侣的作用（Aim 4D）。 该项目利用了由PI Grotewiel（苍蝇）和Miles（小鼠）指导的两个独立实验室的互补专业知识，并设计了几个主要的集成点。Clic 4/Clic最初被Miles实验室对基因表达、连锁和关联数据的一系列分析认为是乙醇行为的候选基因。Grotewiel实验室随后对果蝇中Clic的遗传分析使Clic 4成为小鼠乙醇行为研究的高优先级位点（描述为初步数据）。这些研究合在一起，合理地支持了对Clic/Clic 4如何影响苍蝇（目标1和2）和小鼠（目标4A和4B）的乙醇反应的更广泛的研究。此外，对小鼠乙醇反应基因的其他研究（目标4A和4C）现在正在为研究Clic作用机制的果蝇实验设计提供信息（目标3）。目标3中果蝇研究的结果反过来将指导小鼠实验的设计，研究Clic 4在哺乳动物乙醇行为中的机制（目标4D）。该项目中的故意跨物种整合，在Miles和Grotewiel实验室之间的合作框架内实施，将推动对乙醇行为背后的保守机制进行有力的遗传研究。

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.