Molecular Basis of Excessive Alcohol Drinking

描述(申请人提供)：酒精中毒是一种在世界范围内具有相当高的发病率、死亡率和人类痛苦的疾病，其首要特征是过度饮酒。遗传和环境因素都会导致过量饮酒这一“双击式假说”是我们目前和提议的INIA研究的重点。来自我们目前UO1基金的微阵列结果使我们在了解饮酒的遗传易感性和酒精暴露的分子后果方面取得了实质性进展。通过我们自己的几项研究的重叠，以及重要的是通过INIA的合作，已经确定了重要的候选基因。创建了一个大型的可搜索的开放源代码网络数据库系统，其中包含来自我们研究的3000多万个微阵列数据点，以便于共享酒精中毒研究领域内外的所有数据(2005年在Bergeson等人上公开宣布)。我们目前的目标是继续建立我们的阵列数据库，以包括六个新的INIA小鼠模型的表达分析，专注于鉴定符合我们的“两次击打假说”的候选基因，并利用转基因小鼠和脑区特异性病毒介导的转基因和shRNA表达来测试双向表达(上调和下调)对饮酒的影响。我们将在有无饮酒的情况下进行病毒介导的基因改变后的神经循环特异性微阵列研究，以更好地了解过度饮酒的解剖学和分子贡献。最后，提出了关于miRNA和染色质重塑在饮酒和/或后果中的作用的初步研究。

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.