GABA genes, Alcohol Sensitivity and Alchoholism

描述（由申请人提供）：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（K23）的请求。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受遗传影响的表型，可以更好地了解其原因。酒精通过与氨基酸γ-氨基丁酸（GABA）受体（包括GABAA受体）的相互作用发挥其许多作用，GABAA受体由五种亚基蛋白组装而成，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风险因素，因此本研究将确定GABAA受体亚基基因的遗传变异是否部分介导健康社交饮酒人群中观察到的酒精敏感性差异（具体目标1）。为了检验这一假设，将确定在急性酒精摄入前后反复获得的主观和生理效应的时间过程。具体目标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（如具体目标1中所确定的）是否也与酒精依赖相关。将使用从大量酒精依赖受试者和对照受试者中收集的已建立的DMA数据集来检验这一假设。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酒精使用障碍的筛查和管理。候选人的职业发展计划是在多学科环境中制定的，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，获得心理评估量表应用的经验，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，以磨练技能，作为一个酒精研究人员与人类遗传学的特殊兴趣。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，并具有遗传学方面的专业知识。具体而言，候选人希望为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.