GABA genes, Alcohol Sensitivity and Alchoholism

GABA 基因、酒精敏感性和酗酒

• 批准号: 7448222
• 负责人: Magdalena Uhart
• 金额: $ 2.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448222
• 关键词: Accounting; Acute; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alleles; Amino Acid Receptors; Amino Acids; Biological Assay; Class; Clinical Investigator; Complex; Data Set; Dependence; 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; 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; case control; design; drinking; experience; gamma-Aminobutyric Acid; genetic analysis; interest; multidisciplinary; psychologic; receptor; response; skills; social

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.

描述（由申请人提供）：本申请是申请 NIAAA 指导的以患者为导向的研究职业发展奖 (K23)。酗酒是一种复杂的、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γ-氨基丁酸 (GABA) 受体相互作用来发挥其许多作用，其中包括 GABAA 受体，这些受体由五个亚基蛋白组装而成，参与酒精的增强作用。由于对酒精敏感性的差异是发生酒精使用障碍的一个危险因素，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了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之前和之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 中确定的）是否也与酒精依赖相关。该假设将使用从大量酒精依赖者和对照受试者中收集的既定 DMA 数据集进行检验。这项研究将扩大我们对酗酒风险传播的一种可能机制的理解。希望这些知识将有助于未来筛查和管理酒精使用障碍的药物遗传学方法。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、学习实验室技术以及获得遗传技能分析。尽管候选人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，以磨练作为对人类遗传学特别感兴趣的酒精研究人员的技能。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者。具体来说，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转化应用做出重大贡献。