GABA genes, Alcohol Sensitivity and Alchoholism

GABA 基因、酒精敏感性和酗酒

• 批准号: 7880247
• 负责人: Magdalena Uhart
• 金额: $ 14.53万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7880247
• 关键词: Accounting; Acute; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alleles; Amino Acid Receptors; Amino Acids; Biological Assay; 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; 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

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）：此申请是NIAAA指导的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理解其原因。酒精通过与氨基酸γ-氨基二甲酸（GABA）的受体相互作用（包括GABAA受体）发挥其许多作用，这些受体是由五种亚基蛋白组装而成的，并参与了酒精的增强作用。由于对酒精的敏感性差异是饮酒障碍发展的危险因素，因此这项研究将确定GABAA受体亚基基因基因的遗传变异是否介导了健康的社交饮食人群中观察到的对酒精敏感性的差异（特定目标1）。为了检验这一假设，将确定在急性饮酒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是否与酒精依赖性有关。该假设将使用已建立的DMA数据集进行检验，该数据集从大量的酒精依赖和对照对象中收集。这项研究将扩展我们对可能传播酗酒风险的一种可能机制的理解。希望这种知识将有助于对酒精使用障碍筛查和管理的未来药物遗传学方法。候选人的职业发展计划是在多学科的环境中设定的，其中包括：在上述项目中进行指导研究，在人类受试者研究技术方面发展专业知识，在应用心理评估量表的应用中获得经验，学习实验室技术以及在遗传分析中获得技能。尽管候选人是训练有素的神经内分泌学家，但她需要进行指导的培训，以磨练对人类遗传学特别感兴趣的酒精研究人员的技能。候选人的长期职业目标是成为具有遗传学专业知识的酒精使用障碍领域的独立临床研究者。具体而言，候选人渴望为了解酒精滥用和依赖性的多因素发病机理及其对治疗这些疾病的转化应用做出重大贡献。