Epigenetic modification as a mechanism to produce functional tolerance

表观遗传修饰作为产生功能耐受性的机制

• 批准号: 7919253
• 负责人: NIGEL S ATKINSON
• 金额: $ 33.06万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919253
• 关键词: Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Appearance; Behavior; Binding; Biological Models; Calcium-Activated Potassium Channel; Cirrhosis; Code; Complex; DNA; Data; Disease; Drosophila genus; Drosophila melanogaster; Elements; Enhancers; Epigenetic Process; Ethanol; Excision; Gene Expression; Genes; Genetic; Goals; Grant; Health; Heavy Drinking; Histone Acetylation; Histones; Hypertension; Insecta; Knowledge; Link; Malignant neoplasm of liver; Mammals; Mediating; Metabolism; Methods; Mission; Modeling; Modification; Molecular; Mutation; Pattern; Pharmaceutical Preparations; Phenocopy; Phylogenetic Analysis; Play; Printing; Promoter Regions; Public Health; Rattus; Regulation; Research; Risk; Rodent Model; Role; Sedation procedure; Sequence Analysis; Signal Transduction; Speed; Stroke; Surveys; System; Testing; Time; Transcriptional Regulation; Transgenic Organisms; Work; activating transcription factor; addiction; alcohol response; alcohol sensitivity; base; behavior change; behavioral tolerance; experience; foot; histone modification; homologous recombination; innovation; large-conductance calcium-activated potassium channels; mutant; prevent; public health relevance; relating to nervous system; research study; response; tool; transcription factor

DESCRIPTION (provided by applicant): Alcoholism, a disease of changed behavior, is believed to involve alterations in gene expression. The knowledge gap to be filled is that of understanding how ethanol regulates gene expression to produce behaviors associated with alcoholism. It is our long-term goal to understand the transcriptional mechanisms that underlie ethanol-induced changes in gene expression that produce these behaviors. Functional tolerance, a metabolism-independent reduction in ethanol sensitivity due to prior exposure, is a change in behavior that can cause increased alcohol consumption and speed the path to addiction. Experiments in mammals, worms, and insects show that BK channels play an evolutionarily conserved role in ethanol responsivity. The highly conserved slowpoke (slo) gene encodes BK-type Ca2+-activated K+ channels, which integrate Ca2+ signals and electrical signals and are central to modulating neural activity. In Drosophila, ethanol sedation induces slo gene expression, and this expression has been shown to cause functional rapid tolerance to ethanol sedation. It has recently been shown that epigenetic modification to gene promoter regions underlies important aspects of long-term changes in behavior caused by experience and drugs. These modifications are believed to form an extended code that regulates gene expression. Induction of slo expression has been linked to epigenetic modifications of histones across the promoter region of the gene. The central hypothesis, formed from substantial preliminary data, is that ethanol sedation activates transcription factors and produces histone modifications that together result in increased slo expression to produce tolerance. It is the objective of this proposal to identify the transcription factors and epigenetic histone modifications that cause ethanol-induced slo expression. This objective will be achieved by pursuing the following specific aims: 1) determination of the time course of ethanol- induced histone modifications across the slo promoter region; 2) identification of transcription factors that modify histones and induce slo expression in response to ethanol sedation; and 3) identification of the cis-acting enhancers in the slo promoter region that are used in the ethanol-stimulated modification of histones and that are involved in the induction of slo. This work is innovative because it uses the unique toolset of Drosophila to study the epigenetic regulation of a gene known to underlie functional ethanol tolerance. The research is relevant to the mission of NIH/NIAAA because it has the potential to illuminate the fundamental mechanisms underlying functional tolerance and thereby the path to alcohol addiction. PUBLIC HEALTH RELEVANCE: Alcoholism is a devastating disease that severely impacts public health. Excessive drinking leads to a myriad of health risks, such as stroke, high-blood-pressure, cirrhosis of the liver, and cancer. The proposed research will advance our understanding of how ethanol alters gene expression to produce functional tolerance, an effect that engenders increased alcohol consumption.

描述（由申请人提供）：酗酒，一种行为变化的疾病，被认为涉及基因表达的改变。要填补的知识差距是了解乙醇如何调节基因表达以产生与酒精中毒相关的行为。我们的长期目标是了解乙醇引起的基因表达变化的转录机制，从而产生这些行为。功能耐受性是由于先前暴露而与代谢无关的乙醇敏感性的降低，是行为的变化，可能导致饮酒量增加并加快成瘾的途径。哺乳动物，蠕虫和昆虫的实验表明，BK通道在乙醇反应性中起进化的作用。高度保守的慢速（SLO）基因编码BK型Ca2+激活的K+通道，该通道会整合Ca2+信号和电信号，并且是调节神经活动的核心。在果蝇中，乙醇镇静剂诱导SLO基因表达，并且该表达已被证明会引起对乙醇镇静的功能快速耐受性。最近已经显示，对基因启动子区域的表观遗传修饰是经验和药物引起的长期行为变化的重要方面。这些修饰被认为形成了调节基因表达的扩展代码。 SLO表达的诱导与基因启动子区域的组蛋白的表观遗传修饰有关。由大量初步数据形成的中心假设是，乙醇镇静激活转录因子并产生组蛋白的修饰，从而共同导致SLO表达增加以产生耐受性。该建议的目的是确定引起乙醇诱导的SLO表达的转录因子和表观遗传组蛋白的修饰。该目标将通过追求以下特定目的来实现：1）确定乙醇诱导的整个SLO启动子区域乙醇诱导的组蛋白修饰的时间过程； 2）鉴定转录因子可修饰组蛋白并响应乙醇镇静作用； 3）鉴定SLO启动子区域中的顺式作用增强子，这些增强子用于乙醇刺激的组蛋白修饰，并参与SLO的诱导。这项工作具有创新性，因为它使用果蝇的独特工具集研究了已知的基因的表观遗传调节，该基因已知能够构成功能性乙醇耐受性。这项研究与NIH/NIAAA的使命有关，因为它有可能阐明功能耐受性的基本机制，从而实现酒精成瘾的途径。 公共卫生相关性：酒精中毒是一种严重影响公共卫生的毁灭性疾病。过度饮酒会导致无数的健康风险，例如中风，高血压，肝脏肝硬化和癌症。拟议的研究将促进我们对乙醇如何改变基因表达产生功能耐受性的理解，从而增加了饮酒量。