Molecular Mechanisms of Ethanol-Responsive Myelin Gene Expression

酒精滥用和酒精中毒是一种复杂的疾病，涉及中枢神经系统内的多个信号事件。酒精暴露导致的这些信号通路的变化可能会导致神经适应，从而导致长期的行为后果，如依赖。不足为奇的是，基因是酒精滥用发展的一个已知因素，约占滥用倾向的一半。大量研究试图确定与酒精滥用有关的单基因，但仅显示出适度的成功。我们建议结合遗传学、基因组学和药理学工具来研究这种复杂的特征。例如，DNA微阵列将允许无偏见地同时检查由于乙醇或不同遗传背景而导致的数千个基因的基因表达变化。这种方法有可能识别导致酒精暴露分子适应差异的遗传和基因组变异。我们假设这些变异是控制乙醇诱导的中枢神经系统可塑性事件和随后的行为反应的区域神经生物学差异的原因。 这项研究旨在了解中枢神经系统中乙醇反应髓鞘基因网络的遗传和分子机制，以及它们与酒精行为表型的关系。众所周知，在人类和动物模型中，乙醇都会改变髓鞘基因的表达。将使用药物抑制剂、基因敲除小鼠和微阵列来表征调节急性乙醇反应髓鞘基因表达的分子机制。这项研究的总体目标将通过完成以下具体目标来实现：1)确定Fyn激酶是否调节小鼠前额叶皮质髓鞘相关基因的表达，2)表征Fyn激酶在小鼠前额叶皮质参与急性乙醇反应髓鞘基因表达的扩展信号网络，以及3)确定与髓鞘基因表达相关的酒精相关行为和相应的信号机制。研究急性酒精暴露与髓鞘基因表达有关的分子途径，可能在髓鞘和酒精相关疾病的研究中具有潜在的新意义。

Alcohol abuse and alcoholism is a complex disease involving multiple signaling events within the central nervous system. Changes in these signaling pathways as a result of alcohol exposure may lead to neuroadaptations with long-term behavioral consequences such as dependence. Not surprisingly, genetics are a known factor in the development of alcohol abuse, contributing approximately half of the predisposition for abuse. A large amount of research has attempted to identify single genes associated with ethanol abuse, but has shown only moderate success. We propose combining genetic, genomic, and pharmacological tools to study this complex trait. For example, DNA microarrays will allow an unbiased simultaneous examination of changes in gene expression across several thousand genes due to ethanol or divergent genetic backgrounds. This approach has the possibility of identifying genetic and genomic variation contributing to disparities in the molecular adaptations occurring with ethanol exposure. We hypothesize these variations are responsible for regional neurobiological differences controlling ethanol-induced CNS plastic events and subsequent behavioral responses. The proposed study is aimed at understanding the genetic and molecular mechanisms of ethanol-responsive myelin gene networks in the central nervous system as well as their relationship to ethanol behavioral phenotypes. Myelin gene expression is known to be altered by ethanol in both humans and animal models. Pharmacological inhibitors, genetic knockout mice, and microarrays will be used to characterize the molecular mechanisms regulating acute ethanol-responsive myelin gene expression. The overall goal of this study will be accomplished by completing the following specific aims: 1) Determine if Fyn kinase regulates myelin-associated gene expression in mouse prefrontal cortex, 2) Characterize a Fyn kinase 'extended' signaling network involved in acute ethanol- responsive myelin gene expression in mouse prefrontal cortex, and 3) Identify ethanol-related behaviors associated with myelin gene expression and corresponding signaling mechanisms. Investigating the molecular pathways of acute ethanol exposure involved in myelin gene expression may potentially have novel implications in the study of myelin and ethanol-related disorders.