Control of Alcohol Responses by Actin-Regulating Genes

 描述(由申请人提供)：酒精使用障碍(AUD)是社会上一个重大的健康负担，但其潜在的分子机制仍未被很好地理解。AUDS的风险人群可能对乙醇的有益方面更敏感，和/或对令人厌恶的醉人效应更具抵抗力。虽然AUDS有重要的遗传病因，但很少有已知的基因对这些疾病的发展有重大贡献。对这些效应的分子理解将有助于设计合理的干预策略，黑腹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。这项建议的目标是研究调控肌动蛋白细胞骨架的基因，以及它们实现这一目的的分子机制，以调控果蝇的酒精诱导行为。拟议的实验建立在我们之前的发现基础上，即Rho家族小GTPase rac1的负调控因子Rsu1在不同的神经元中是必需的，以调节对酒精的天真厌恶，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，以及介导单纯酒精厌恶和经验依赖型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，并测试它们与酒精厌恶和偏好的关系。这将包括对肌动蛋白调节蛋白及其在这些多巴胺能神经元中的作用的研究。第三，我们将研究多巴胺能信号与rac1调控的分子机制。这将包括对多巴胺受体和已知的rac1调节蛋白在酒精偏好和厌恶中所起作用的研究。我们建议研究的基因从果蝇到哺乳动物都高度保守，其中一些我们已经确定的基因具有与饮酒和依赖相关的人类变体。这项拟议的研究将促进我们对AUDS发生的遗传基础的理解。这反过来将导致确定新的危险因素和治疗酒精滥用障碍的潜在治疗目标。

 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.