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: 8066700
• 负责人: Sean P Farris
• 金额: $ 4.03万
• 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/8066700
• 关键词: Acute; Affect; Alcohol abuse; Alcohol-Related Disorders; Alcoholism; Animal Model; Axon; Behavior; Behavioral; Bioinformatics; Complex; DNA Microarray Chip; Data; Data Analyses; Dependence; Development; Disease; Dose; Ethanol; Ethanol toxicity; Event; Exhibits; Gene Expression; Gene Proteins; Gene-Modified; Genes; Genetic; Genome; Genomics; Genotype; Goals; Health; Human; Inbred Strains Mice; Individual; Knockout Mice; Laboratories; Lead; Measures; Mediating; Microarray Analysis; Modeling; Molecular; Molecular Genetics; Mus; Myelin; Neuraxis; Neurobiology; Neuroglia; Neuronal Plasticity; Neurons; Pathway interactions; Pattern; Pharmacotherapy; Phenotype; Phosphotransferases; Plastics; Play; Predisposition; Prefrontal Cortex; Proto-Oncogene Proteins c-fyn; Recombinants; Regulation; Research; Resources; Role; Saline; Schizophrenia; Signal Pathway; Signal Transduction; Testing; Time; Variant; Western Blotting; addiction; alcohol behavior; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; base; genetic inhibitor; genetic resource; kinase inhibitor; mouse model; myelination; nervous system disorder; neuroadaptation; neurotransmission; neurotransmitter release; novel; protein expression; response; success; tool; trait

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.

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事件。这些信号通路的变化作为酒精暴露的结果可能会导致神经适应与长期的行为后果，如依赖。毫不奇怪，遗传学是酒精滥用发展的一个已知因素，约占滥用倾向的一半。大量的研究试图确定与乙醇滥用相关的单个基因，但只取得了一定的成功。我们建议结合遗传学，基因组学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遗传背景而引起的数千个基因的基因表达变化进行无偏的同时检查。这种方法有可能识别遗传和基因组变异，导致乙醇暴露发生的分子适应差异。我们假设这些变化是负责区域神经生物学差异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。 这项拟议的研究旨在了解中枢神经系统中乙醇响应性髓鞘基因网络的遗传和分子机制，以及它们与乙醇行为表型的关系。在人类和动物模型中，乙醇都能改变髓鞘基因的表达。药理学抑制剂，基因敲除小鼠和微阵列将被用来表征调节急性乙醇反应髓鞘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叶皮层中的髓鞘相关基因表达，2）表征参与小鼠前额叶皮层中急性乙醇响应性髓鞘基因表达的Fyn激酶“延伸”信号传导网络，和3）鉴定与髓鞘基因表达相关的乙醇相关行为和相应的信号传导机制。研究急性乙醇暴露参与髓鞘基因表达的分子途径可能对髓鞘和乙醇相关疾病的研究产生新的影响。