Molecular Basis of Excessive Alcohol Drinking

酒精中毒是一种在世界范围内发病率、死亡率和人类痛苦都很大的疾病，是世界上第一个和 以过度饮酒为主要特征。“两次命中假说”认为基因和 环境因素导致过度饮酒是我们当前和 建议进行INIA研究。我们目前UO1基金的微阵列结果已经取得了很大进展 对饮酒遗传易感性和分子水平的理解 酒精暴露的后果。已经确定了重要的候选基因，尽管重叠的 我们自己的几项研究，更重要的是通过INIA的合作。一个大型的、可搜索的、开源的 我们创建了包含3000多万个来自我们研究的微阵列数据点的基于Web的数据库系统 使酒精中毒研究领域内外的所有数据共享变得容易(在 Bergeson等人，2005年)。我们目前的目标是继续构建我们的阵列数据库，以包括 六个新的INIA小鼠模型的表达分析，重点是鉴定与我们的 “两击假说”，并利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，以测试双向表达(上调和下调)对饮酒的影响。 我们将在病毒介导的基因变化后进行神经回路特异性微阵列研究 饮酒的存在和不存在，以更好地了解解剖学和分子生物学的作用 过度饮酒。最后，最初的研究集中在miRNA和染色质重塑在 饮酒和/或后果被提出。

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.