GABA genes, Alcohol Sensitivity and Alchoholism

描述(由申请者提供)：此申请是对NIAAA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、受基因影响的疾病，通过研究介导风险的受基因影响的表型可以更好地了解其原因。酒精的许多作用是通过与氨基酸γ-氨基丁酸(GABA)的受体相互作用实现的，包括GABAA受体，GABAA受体是由五个亚单位蛋白质组装形成的，参与了酒精的增强作用。由于对酒精的敏感性差异是酒精使用障碍发展的风险因素，这项研究将确定GABAA受体亚单位基因的遗传变异是否在一定程度上调节了在健康的社交饮酒人群中观察到的对酒精敏感性的差异(特定目标1)。为了验证这一假设，将确定在急性酒精摄入之前和之后反复获得的主观和生理影响的时间进程。特定目标2将确定与酒精敏感性差异相关的GABAA受体亚单位基因的遗传变异(在特定目标1中确定)是否也与酒精依赖有关。这一假设将使用从大量酒精依赖和对照受试者中收集的已建立的DMA数据集进行验证。这项研究将扩大我们对酒精中毒风险传播的一种可能机制的理解。希望这些知识将有助于今后在酒精使用障碍的筛查和管理中采用药物遗传学方法。应聘者的职业发展计划是在一个多学科的环境中制定的，包括：在上述项目中进行指导性研究，发展人类受试者研究技术方面的专业知识，获得心理评估量表的应用经验，学习实验室技术，获得基因分析技能。尽管应聘者是一位训练有素的神经内分泌学家，但她需要接受指导培训，以磨练对人类遗传学特别感兴趣的酒精研究人员的技能。这位候选人的长期职业目标是成为酒精使用障碍领域的一名具有遗传学专业知识的独立临床研究员。具体地说，候选人渴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翻译应用做出重大贡献。

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.