Molecular Mechanisms of Ethanol-Responsive Myelin Gene Expression

乙醇响应性髓磷脂基因表达的分子机制

• 批准号: 7912124
• 负责人: Sean P Farris
• 金额: $ 3.98万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-25 至 2012-03-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912124
• 关键词: Acute; Affect; Alcohol abuse; Alcohol-Related Disorders; Alcoholism; Animal Model; Behavioral; Complex; DNA Microarray Chip; Dependence; Development; Disease; Ethanol; Event; Gene Expression; Genes; Genetic; Genomics; Goals; Health; Human; Individual; Knockout Mice; Lead; Molecular; Molecular Genetics; Mus; Myelin; Neuraxis; Neurobiology; Pathway interactions; Pharmacotherapy; Phenotype; Phosphotransferases; Plastics; Predisposition; Prefrontal Cortex; Research; Signal Pathway; Signal Transduction; Variant; alcohol behavior; alcohol exposure; genetic inhibitor; neuroadaptation; novel; public health relevance; response; success; tool; trait

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Alcohol abuse and alcoholism significantly affects the health millions of individuals worldwide, however, few effective pharmacotherapies exist to date. Developing newer therapies will require understanding the molecular mechanisms associated with acute and long-term ethanol exposure.

描述（由申请人提供）：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种信号传导事件。暴露于酒精导致这些信号通路的变化可能会导致神经适应，从而产生依赖等长期行为后果。毫不奇怪，遗传是导致酗酒的一个已知因素，大约一半的酗酒倾向是由遗传因素造成的。大量研究试图识别与乙醇滥用相关的单个基因，但只取得了一定的成功。我们建议结合遗传、基因组和药理学工具来研究这种复杂的性状。例如，DNA 微阵列将允许对由于乙醇或不同的遗传背景而导致的数千个基因的基因表达变化进行公正的同步检查。这种方法有可能识别导致乙醇暴露后分子适应差异的遗传和基因组变异。我们假设这些变化是控制乙醇诱导的中枢神经系统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。 拟议的研究旨在了解中枢神经系统中乙醇反应性髓磷脂基因网络的遗传和分子机制及其与乙醇行为表型的关系。已知在人类和动物模型中，乙醇会改变髓磷脂基因的表达。药理学抑制剂、基因敲除小鼠和微阵列将用于表征调节急性乙醇反应性髓磷脂基因表达的分子机制。本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皮质中髓磷脂相关基因的表达，2) 表征参与急性乙醇反应的 Fyn 激酶“扩展”信号网络小鼠前额皮质中的髓磷脂基因表达，以及3) 识别与髓磷脂基因表达和相应信号机制相关的乙醇相关行为。研究与髓磷脂基因表达有关的急性乙醇暴露的分子途径可能对髓磷脂和乙醇相关疾病的研究具有新的意义。 公共卫生相关性：酒精滥用和酒精中毒严重影响全世界数百万人的健康，但是迄今为止，有效的药物疗法很少。开发新的疗法需要了解与急性和长期乙醇暴露相关的分子机制。