IRPG1 R01 NOVEL PHENOTYPES FOR THE GENETIC ANALYSIS

酒精依赖者的临床症状的数量和种类通常会导致很大的异质性。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并不是最理想的。在这项应用中，我们建议根据与酒精中毒相关的神经生物学和神经行为特征来开发基本的内表型。我们假设神经去抑制是酒精中毒发展过程中的一个中心生物学特征。我们建议使用一套新的神经电学特征，专门为评估高密度酒精中毒家庭的去抑制而设计。我们计划使用功能磁共振成像方法来定位特定的神经源，并使用氟马西尼进行PET研究(华盛顿大学和纽约州立大学)，以评估高风险和低风险受试者之间发生酒精中毒的结合位点(GABA)的潜在差异。我们建议使用口服酒精挑战(UCSD)和一种新开发的酒精夹住技术(印第安纳大学和霍华德大学)来评估酒精对几种解除抑制措施的影响。除了使用目前可用的诊断标准外，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。此外，我们计划使用一份详细的问卷来评估饮酒的数量和频率以及饮酒模式。所有提出的新的内表型都是定量的，代表了我们的IRPG的本质。我们还建议对非洲裔美国家庭人口中的上述变量进行评估。涉及标准化文书和程序的互动研究活动将在七个不同地点进行，具体资源在提案中所述共享。最后，第八个IRPG站点(罗格斯大学)将负责DNA提取和细胞系，以及一个主要的存储库。

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.