IRPG1 R01 NOVEL PHENOTYPES FOR THE GENETIC ANALYSIS

酒精依赖个体的临床症状的数量和种类通常导致大量的异质性。 因此，在酒精中毒的遗传学研究中，使用诊断作为表型描述符可能不是最佳的。 在本申请中，我们建议开发基于与酒精中毒相关的神经生物学和神经行为学特征的基本内表型。 我们假设神经抑制解除是酒精中毒发展的一个重要生物学特征。 我们建议使用一套新的神经电功能，专门设计用于评估高密度酗酒家庭的抑制解除。 我们计划使用功能磁共振成像方法定位特定的神经源，并进行PET研究（华盛顿大学和纽约州立大学）与氟马西尼，以评估潜在的差异，结合位点（GABA）之间的高风险和低风险的受试者发展成酒精中毒。 我们建议使用口服酒精挑战（UCSD）和新开发的酒精钳夹技术（印第安纳州大学和霍华德大学）来评估酒精对几种去抑制措施的影响。 除了使用现有的诊断标准外，我们还将使用一些量表来评估酒精敏感性，耐受性，渴望和依赖性。此外，我们计划使用一份详细的问卷调查，评估酒精摄入量和频率以及饮酒模式。 所有提出的新型内表型都是代表我们IRPG本质的定量指标。 我们还建议在非裔美国人家庭的人口中评估上述变量。 将在七个不同的地点利用提案中所述的具体共享资源开展涉及标准化工具和程序的交互式研究活动。 最后，第八个IRPG站点（罗格斯大学）将负责DNA提取和细胞系，以及一个主要的储存库。

The number and variety of clinical symptoms noted in alcohol dependent individuals typically result in a great deal of heterogeneity. Therefore, the use of diagnosis may not be optimal as a phenotypic descriptor in genetic studies of alcoholism. In this application we propose to develop fundamental endophenotypes based on neurobiological and neurobehavioral characteristics associated with alcoholism. We hypothesize that neural disinhibition is a central biologic feature in the development of alcoholism. We propose to use a novel set of neuroelectric features specifically designed to assess disinhibition in families with a high density of alcoholism. We plan to use fMRI methods to localize specific neural sources, and to conduct PET studies (Washington University and SUNY) with flumazenil to assess potential differences in binding sites (GABA) between subjects at high and low risk to develop alcoholism. We propose to assess the effects of alcohol on several measures of disinhibition using an oral alcohol challenge (UCSD), and a newly developed alcohol clamping technique (Indiana University and Howard University). In addition to the use of currently available diagnostic criteria, we will use a number of scales to assess alcohol sensitivity, tolerance, craving and dependence. Moreover, we plan to use a detailed questionnaire assessing quantity and frequency of alcohol intake as well as pattern of drinking. All of the proposed novel endophenotypes are quantitative measures which represent the essence of our IRPG. We also propose to assess the above mentioned variables in a population of African-American families. Interactive research activity dealing with standardized instruments and procedures will be carried out at seven different sites with specific shared resources described in the proposal. Finally, the eighth IRPG site (Rutgers University) will be responsible for DNA extraction and cell lines, as well as a major repository.