Molecular Basis of Excessive Alcohol Drinking

酒精中毒是一种在全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， 最主要的特征是过度饮酒。“两次打击假说”认为，基因和 环境因素导致过量酒精摄入是我们目前的首要重点， INIA的研究。我们目前的UO 1资助的微阵列结果已经允许了实质性的进展， 使我们能够理解饮酒的遗传倾向和 酒精暴露的后果。重要的候选基因已被确定，虽然重叠的 我们自己的几项研究，以及重要的INIA合作。一个大型的可搜索的开源 我们创建了一个基于网络的数据库系统，其中包含来自我们研究的超过3000万个微阵列数据点， 使酗酒研究领域内外的所有数据共享变得容易（在2009年公开宣布）。 Bergeson等人，2005年）。我们当前的目标是继续构建阵列数据库， 六个新的INIA小鼠模型的表达分析，集中在表征候选基因，适合我们的研究。 “两击假说”，并使用基因改变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改变后进行神经回路特异性微阵列研究。 存在和不存在饮酒，以更好地了解解剖和分子贡献， 过量饮酒。最后，最初的研究集中在miRNA和染色质重塑在细胞凋亡中的作用。 饮酒和/或后果。

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.