Defining the metabolic-epigenetic regulation of neuronal chromatin by alcohol

定义酒精对神经元染色质的代谢表观遗传调节

• 批准号: 10921075
• 负责人: Philipp Mews
• 金额: $ 23.73万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10921075
• 关键词: Acetaldehyde; Acetates; Acetyl Coenzyme A; Acetylation; Adult; Affect; Alcohol consumption; Alcohol dehydrogenase; Alcohol dependence; Alcohols; Animal Model; Animals; Award; Behavior; Behavioral; Binding; Biological Assay; Brain; Brain Diseases; Chromatin; Chronic; Complement; Consummatory Behavior; Consumption; Coupled; Darkness; Data; Deposition; Development; Disease; Drug Addiction; Enzymes; Epigenetic Process; Ethanol Metabolism; Etiology; Family; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Goals; Grant; Hepatic; Hippocampus; Histone Acetylation; Histones; Injections; Intoxication; Investigation; Learning; Link; Liver; Lysine; Mediating; Memory; Mentors; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Nature; Neurobiology; Neurons; Nuclear; Pathologic; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Play; Process; Proteins; Public Health; Research; Rodent; Role; Scientist; Signal Transduction; Societies; Stimulus; Technical Expertise; Testing; Therapeutic Intervention; Training; Transcriptional Regulation; United States National Institutes of Health; Viral; Viral Vector; Work; addiction; alcohol abuse therapy; alcohol effect; alcohol response; alcohol use disorder; behavioral response; binge drinking; career; clinically relevant; comparison control; cost; defined contribution; drinking; drinking behavior; epigenetic regulation; epigenomics; extracellular; fomepizole; gene function; genetic manipulation; genome-wide; human model; in vivo; information processing; inhibitor; innovation; knock-down; learned behavior; memory process; neural; neurotransmission; new therapeutic target; novel; overexpression; peripheral blood; programs; recruit; reward circuitry; social; transcription factor; transcriptome sequencing; treatment strategy

Project Summary Addiction to alcohol represents a major public health issue exacting tremendous financial and social costs. Despite this, alcohol addiction remains a recalcitrant condition with conventional pharmacotherapies lacking substantial and durable efficacy. Much of the existing research into the neurobiology and treatment of alcohol addiction has focused on limbic reward circuitry, changes in neurotransmission, and intracellular neuronal signaling cascades. However, in recent years there has been a surge in research examining the role of epigenetic factors in the development of pathological alcohol use disorders. Epigenetic control of gene expression plays a critical role in processing neural activity in the adult brain, and there is clear evidence in humans and animal models that link changes in brain chromatin to addiction. In recent years, chromatin-bound metabolic enzymes have emerged as central players in epigenetic regulation, leading to a fundamental shift in models of transcriptional regulation, and implicating epigenetic-metabolic processes in the molecular and behavioral response to alcohol. This NIH Pathway to Independence Award (K99/R00) will significantly facilitate the candidate’s, Dr. Mews, ability to begin his career as an independent scientist, allowing him to study new perspectives of this metabolic-epigenetic gene regulation by alcohol, and to explore epigenetic factors as novel therapeutic targets in alcohol use disorders. In the mentored K-phase of this grant (Specific Aim 1 and Specific Aim 2), the contribution of peripheral alcohol metabolism in the liver to histone acetylation in the brain will be determined in a translationally relevant binge drinking model in rodents. Alcohol-induced histone acetylation will be assayed both locally and globally in the hippocampus, a region intimately linked to alcohol addiction vulnerability, and the direct modulation of gene expression by alcohol-derived acetate that originates in hepatic alcohol metabolism will be tested. Further, viral manipulation of gene expression to manipulate acetyl-CoA metabolism will be used to establish causality and determine whether the metabolic-epigenetic ACSS2 pathway links alcohol-driven histone acetylation to increased consumption and alcohol-related learning. In the independent phase (R00), Specific Aim 3, we will combine these conceptually and technically innovative approaches with translational binge drinking models to investigate the chromatin-based targeting mechanisms that allow ACSS2 to regulate specific gene expression induced by alcohol in the brain. In summary, the research proposed in this Pathway to Independence Award will illuminate the metabolic-epigenetic mechanisms by which alcohol influences neuronal processes as well as alcohol-related learning and drinking behavior; while simultaneously preparing the candidate with an unique set of intellectual and technical skills that will allow him to develop a fully independent research program on alcohol addiction that is capable of integrating a wide range of neuroepigenetic and behavioral approaches in a technically advanced and high impact manner.

项目摘要 酗酒是一个重大的公共卫生问题，造成巨大的经济和社会代价。 尽管如此，酒精成瘾仍然是一种顽固性疾病，缺乏传统的药物治疗。 实质和持久的功效。现有的许多关于神经生物学和酒精治疗的研究 成瘾主要集中在边缘奖赏回路、神经传递的改变和细胞内神经元。 信号级联。然而，近年来，考察表观遗传学作用的研究激增。 病理性酒精使用障碍发生的因素。基因表达的表观遗传控制起着重要作用 在成人大脑中处理神经活动的关键作用，在人类和动物中有明确的证据 将大脑染色质变化与成瘾联系起来的模型。近年来，染色质结合的代谢酶 已经成为表观遗传调控的核心参与者，导致了 转录调控和分子和行为中的表观遗传-代谢过程 对酒精的反应。NIH独立之路奖(K99/R00)将极大地促进 候选人Mews博士有能力作为一名独立科学家开始他的职业生涯，使他能够研究新的 酒精对这种代谢-表观遗传基因调控的前景，并探索新的表观遗传因素 酒精使用障碍的治疗靶点。在这笔赠款的指导K阶段(具体目标1和具体目标 目的2)，肝脏外周酒精代谢对脑中组蛋白乙酰化的贡献将是 在啮齿动物的一种翻译相关的狂饮模型中确定的。酒精诱导的组蛋白乙酰化将 在与酒精成瘾密切相关的海马区进行局部和全局检测 脆弱性，以及起源于肝脏的酒精衍生醋酸酯对基因表达的直接调控 酒精新陈代谢将进行测试。此外，病毒操纵基因表达以操纵乙酰辅酶A 新陈代谢将用于建立因果关系，并确定新陈代谢-表观遗传ACSS2途径 将酒精驱动的组蛋白乙酰化与增加的消费量和酒精相关的学习联系起来。在 独立阶段(R00)，具体目标3，我们将结合这些概念和技术创新 利用翻译型狂饮模型研究染色质靶向机制的方法 这使得ACSS2能够调节酒精诱导的大脑中特定基因的表达。总而言之，这项研究 在这条通往独立的道路奖中提出的将阐明代谢-表观遗传机制 酒精影响神经过程以及与酒精相关的学习和饮酒行为；而 同时使候选人具备一套独特的智力和技术技能，这将使他 开发一个完全独立的酒精成瘾研究计划，能够整合广泛的范围 以技术先进和高影响力的方式对神经表观遗传学和行为方法进行研究。