GABA genes, Alcohol Sensitivity and Alchoholism

此应用程序是一个NIAAA指导以患者为导向的研究职业发展奖的要求 （K23）。酒精中毒是一种复杂的、受遗传影响的疾病， 通过研究介导风险的遗传影响表型。酒精发挥了许多作用， 通过与氨基酸γ-氨基丁酸（GABA）受体相互作用产生的效应，包括 GABAA受体由五个亚基蛋白组装而成，参与了 酒精的强化作用。因为对酒精敏感性的差异是发展的风险因素 这项研究将确定GABAA受体亚基基因的遗传变异是否与酒精使用障碍有关， 在健康的社交饮酒人群中， （具体目标1）。为了验证这一假设，主观和生理效应的时间过程， 在急性酒精摄入之前和之后重复测定。具体目标2将确定是否 GABAA受体亚基基因的遗传变异与对酒精的敏感性差异相关（如 具体目标1）也与酒精依赖有关。这一假设将得到检验 使用从大量酒精依赖和对照人群中收集的已建立的DMA数据集， 这项研究将扩大我们对酗酒风险的一种可能机制的理解， 可以被传输。希望这些知识将有助于未来的药物遗传学方法， 酒精使用障碍的筛查和管理。候选人的职业发展计划在 一个多学科的环境，包括：在上述项目中进行指导研究， 发展人类受试者研究技术的专业知识，获得应用 心理评估量表，学习实验室技术，并获得遗传分析技能。 虽然候选人是一个训练有素的神经内分泌学家，她需要指导培训，磨练技能 作为一个对人类遗传学特别感兴趣的酒精研究者。候选人的长期职业目标是 成为酒精使用障碍领域的独立临床研究者，并拥有遗传学方面的专业知识。 具体来说，候选人渴望为理解多因素 酒精滥用和依赖的发病机制及其治疗这些疾病的转化应用。

This application is a request for a NIAAA Mentored Patient-Oriented Research Career Development Award (K23). Alcoholism is a complex, genetically influenced disorder the cause of which may be better understood through the study of genetically influenced phenotypes that mediate the risk. Alcohol exerts many of its effects via interactions with receptors for the amino acid gamma-aminobutyricacid (GABA), including GABAA receptors, which are formed by the assembly of five subunit proteins and are involved in the reinforcing effects of alcohol. Because differences in sensitivity to alcohol is a risk factor for the development of alcohol use disorders, this study will determine if genetic variation in GABAA -receptor subunit genes mediate, in part, the observed variance in sensitivity to alcohol in a healthy social-drinking population (Specific Aim 1). To test this hypothesis, the time course of subjective and physiological effects obtained repeatedly before and following acute alcohol ingestion will be determined. Specific Aim 2 will determine if genetic variations in GABAA-receptor subunit genes associated with differences in sensitivity to alcohol (as determined in Specific Aim 1) are also associated with alcohol dependence. This hypothesis will be tested using an established DMAdataset collected from a large population of alcohol-dependent and control subjects.This research will expand our understanding of one possible mechanism by which risk of alcoholism may be transmitted. It is hoped that such knowledge will contribute to future pharmacogenetic approaches in the screening and management of alcohol use disorders. The candidate's career development plan is set in a multidisciplinary environment and includes: conducting mentored research in the project described above, developing expertise in human subjects research techniques, acquiring experience in the application of psychological assessment scales, learning laboratory techniques, and gaining skills in genetic analysis. Although the candidate is a well-trained neuroendocrinologist, she requires mentored training to hone skills as an alcohol researcher with a special interest in human genetics. The candidate's long term career goal is to become an independent clinical investigator in the field of alcohol use disorders with expertise in genetics. Specifically, the candidate aspires to make significant contributions to understanding the multifactorial pathogenesis of alcohol abuse and dependence and its translational application to treating these disorders.