GABA genes, Alcohol Sensitivity and Alchoholism

GABA 基因、酒精敏感性和酗酒

• 批准号: 8284475
• 负责人: Magdalena Uhart
• 金额: $ 15.03万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284475
• 关键词: Accounting; Acute; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alleles; Amino Acid Receptors; Amino Acids; Biological Assay; Clinical Investigator; Complex; Development; Development Plans; Diagnosis; Disease; Dose; Environment; Family; Feeling; Future; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Goals; Haplotypes; Heart Rate; Human Genetics; Human Subject Research; Individual; Knowledge; Laboratories; Learning; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; National Institute on Alcohol Abuse and Alcoholism; Neuraxis; Pathogenesis; Pharmacogenetics; Phenotype; Physiological; Population; Population Control; Protein Subunits; Psychosocial Factor; Receptor Gene; Recruitment Activity; Reporting; Research; Research Personnel; Research Proposals; Research Technics; Risk; Risk Factors; Sampling; Screening procedure; Single Nucleotide Polymorphism; Stratification; Techniques; Testing; Time; Training; Variant; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; alcohol use disorder; base; career; career development; case control; design; drinking; experience; gamma-Aminobutyric Acid; genetic analysis; genetics of alcoholism; interest; multidisciplinary; psychologic; receptor; response; skills; social

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.

此申请是对NIAAA指导的以患者为导向的研究职业发展奖的请求 (K23)。酒精中毒是一种复杂的、受基因影响的疾病，其原因可能更好地被理解 通过对影响风险的遗传表型的研究。酒精会使它的许多方面 通过与氨基酸γ-氨基丁酸(GABA)受体的相互作用产生的影响，包括 GABAA受体，由五个亚基蛋白组装而成，参与 酒精的强化作用。因为对酒精的敏感度不同是发展的一个危险因素 对于酒精使用障碍，这项研究将确定GABAA受体亚单位基因的遗传变异 在一定程度上，调节了观察到的健康社交饮酒人群对酒精敏感性的差异 (具体目标1)。为了验证这一假设，获得了主观和生理效应的时间进程 在急性酒精摄取之前和之后反复进行检测。具体目标2将决定是否 GABAA受体亚单位基因的遗传变异与酒精敏感性的差异(AS 在具体目标1)中确定的酒精也与酒精依赖有关。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酒精中毒风险的一种可能机制的理解 可能会被传输。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。应聘者的职业发展计划是在 多学科环境，包括：在上述项目中进行指导性研究， 开发人体学科研究技术方面的专业知识，获得应用 心理评估量表，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来磨练技能。 作为一名对人类遗传学特别感兴趣的酒精研究人员。候选人的长期职业目标是 成为酒精使用障碍领域具有遗传学专业知识的独立临床研究员。 具体地说，候选人渴望对理解多因素做出重大贡献 酒精滥用和依赖的发病机制及其在治疗这些疾病中的翻译应用。