Control of Alcohol Responses by Actin-Regulating Genes

描述（由申请人提供）：酒精使用障碍（AUD）是社会的重大健康负担，但其潜在的分子机制仍不清楚。有AUD风险的人可能对乙醇的奖励方面更敏感，和/或对令人厌恶的中毒作用更有抵抗力。虽然AUDs有显着的遗传病因学，很少有基因是已知的，显着有助于这些疾病的发展。对这些效应的分子理解将允许设计合理的干预策略，果蝇已经成为了解酒精行为反应的分子机制的越来越有用的模型。这个计划的目标是研究调节肌动蛋白细胞骨架的基因，以及它们调节乙醇诱导的果蝇行为的分子机制。这些实验建立在我们之前的发现基础上，即Rsu 1是小Rho家族GTdR Rac 1的负调节因子，在不同的神经元中需要介导对酒精的天真厌恶或对酒精的经验依赖性偏好。首先，我们将研究多巴胺能神经元，以及介导天真酒精厌恶和经验依赖性酒精偏好的神经回路。其次，我们将研究这些多巴胺神经元的靶神经元，并测试它们在酒精厌恶和偏好中的参与。这将包括肌动蛋白调节剂的研究，以及它们在这些多巴胺能神经元中的作用。第三，我们将研究多巴胺能信号转导与Rac 1调控之间的分子机制。这将包括多巴胺受体的调查，和已知的Rac 1调节蛋白在酒精偏好和厌恶的作用。我们打算研究的基因从果蝇到哺乳动物都是高度保守的，我们已经描述的一些基因具有与酒精消费和依赖相关的人类变异。拟议的研究将促进我们对AUDs发展的遗传基础的理解。这反过来将导致识别新的风险因素和潜在的治疗目标，用于治疗酒精滥用障碍。

DESCRIPTION (provided by applicant): Alcohol use disorders (AUD) are a significant health burden on society, yet the underlying molecular mechanisms are still not well understood. People at risk for AUDs can be more sensitive to the rewarding aspects of ethanol, and/or more resistant to the aversive intoxicating effects. Although AUDs have significant genetic etiology, few genes are known that significantly contribute to the development of these disorders. Molecular understanding of these effects will allow the design of rational interventional strategies, Drosophila melanogaster has become an increasingly useful model to understand the molecular mechanisms of the behavioral responses to alcohol. The goal of this proposal is to study genes regulating the actin cytoskeleton, and the molecular mechanisms by which they do so, to regulate ethanol-induced behaviors in Drosophila. The proposed experiments build on our previous findings that Rsu1, a negative regulator of the small Rho-family GTPase Rac1, is required in distinct neurons to mediate naïve aversion to alcohol, or experience-dependent preference for alcohol. First, we will study the dopaminergic neurons, and neural circuits that mediate naïve alcohol aversion and experience-dependent alcohol preference. Second, we will investigate the target neurons of these dopamine neurons, and test their involvement in alcohol aversion and preference. This will include the study of actin regulators, and their role, in these dopaminergic neurons. Third, we will investigate the molecular mechanism that link dopaminergic signaling to the regulation of Rac1. This will include an investigation of dopamine receptors, and of known Rac1 regulator proteins for their role in alcohol preference and aversion. The genes we propose to investigate are highly conserved from Drosophila to mammals, and some of the ones we have already characterized have human variants that are associated with alcohol consumption and dependence. The proposed research will advance our understanding of the genetic basis for the development of AUDs. This in turn, will result in the identification of new risk factors and potential therapeutic targets for the treatment of alcohol abuse disorders.