Molecular Basis of Excessive Alcohol Drinking

描述（由申请人提供）：酗酒是全世界发病率、死亡率和人类痛苦都很高的一种疾病，其首要特征是过度饮酒。“双重打击假说”认为遗传和环境因素都会导致过量饮酒，这是我们当前和拟议的INIA研究的首要重点。我们目前u01资助的微阵列结果已经使我们对饮酒的遗传易感性和酒精暴露的分子后果的理解取得了实质性进展。通过我们自己的几项研究的重叠，以及重要的INIA合作，已经确定了重要的候选基因。我们创建了一个大型的可搜索的、开源的基于网络的数据库系统，其中包含了来自我们研究的超过3000万个微阵列数据点，以方便地共享酗酒研究领域内外的所有数据（Bergeson等人，2005年公开宣布）。我们目前的目标是继续建立我们的阵列数据库，包括六种新的INIA小鼠模型的表达分析，专注于描述符合我们的“双击假说”的候选基因，并使用转基因小鼠和脑区域特异性病毒介导的转基因和shRNA表达来测试双向表达（上下调节）对饮酒的影响。我们将进行神经回路特异性微阵列研究，跟踪在饮酒和不饮酒的情况下病毒介导的基因变化，以更好地了解过量饮酒的解剖学和分子作用。最后，初步研究的重点是miRNA和染色质重塑在饮酒和/或后果中的作用。

DESCRIPTION (provided by applicant): Alcoholism, a disease of considerable morbidity, mortality and human suffering worldwide, is first and foremost characterized by excessive alcohol drinking. The "Two-Hit hypothesis" that both genetic and environmental factors contribute to excessive alcohol intake is the overarching focus of our current and proposed INIA research. Microarray results from our present UO1 funding have allowed substantial inroads to be made into the understanding of both the genetic predisposition to drink and the molecular consequences of alcohol exposure. Significant candidate genes have been identified though the overlap of several of our own studies and importantly across INIA collaborations. A large searchable, open source web-base database system containing over 30 million microarray data points from our studies was created to make sharing all data within and beyond the alcoholism research field facile (publicly announced in Bergeson et al., 2005). Our current objectives are to continue to build our array database to include expression analyses of six new INIA mouse models, focus us on characterizing candidate genes that fit our "two-hit hypothesis", and to use genetically altered mice and brain region specific viral mediated trans- gene and shRNA expression to test bi-directional expression (up and down regulation) effects on alcohol drinking. We will perform neurocirciutry specific microarray studies following viral-mediated gene changes in the presence and absence of alcohol drinking to better understand anatomical and molecular contributions to excessive alcohol drinking. Finally, initial studies focused on the role of miRNA and chromatin remodeling in alcohol drinking and/or consequences are proposed.