GABA genes, Alcohol Sensitivity and Alchoholism

描述（由申请人提供）：本申请是NIAAA指导患者导向研究职业发展奖（K23）的申请。酒精中毒是一种复杂的、受遗传影响的疾病，其原因可以通过研究介导风险的受遗传影响的表型来更好地理解。酒精通过与氨基酸γ -氨基丁酸（GABA）受体的相互作用发挥其许多作用，包括GABAA受体，GABAA受体由五个亚基蛋白组装而成，并参与酒精的强化作用。由于对酒精敏感性的差异是酒精使用障碍发展的一个危险因素，本研究将确定GABAA受体亚基基因的遗传变异是否在一定程度上介导了健康社交饮酒人群中观察到的对酒精敏感性的差异（具体目标1）。为了验证这一假设，将确定急性饮酒前后反复获得的主观和生理效应的时间过程。特异性目标2将确定与酒精敏感性差异相关的gabaa受体亚基基因的遗传变异（如特异性目标1中确定的）是否也与酒精依赖有关。这一假设将使用从大量酒精依赖者和对照受试者中收集的已建立的DMA数据集进行检验。这项研究将扩大我们对酗酒风险可能传播的一种可能机制的理解。希望这些知识将有助于未来的药物遗传学方法在筛查和管理酒精使用障碍。候选人的职业发展计划设定在多学科环境中，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方面的专业知识，获得心理评估量表应用方面的经验，学习实验室技术，并获得基因分析方面的技能。尽管这位候选人是一位训练有素的神经内分泌学家，但作为一名对人类遗传学有特殊兴趣的酒精研究人员，她需要接受有指导的培训来磨练技能。候选人的长期职业目标是成为具有遗传学专长的酒精使用障碍领域的独立临床研究者。具体来说，候选人渴望对理解酒精滥用和依赖的多因素发病机制及其在治疗这些疾病中的转化应用做出重大贡献。

DESCRIPTION (provided by applicant): 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 DMA dataset 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.