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: 10054232
• 负责人: Philipp Mews
• 金额: $ 15.56万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054232
• 关键词: Acetaldehyde; Acetates; Acetyl Coenzyme A; Acetylation; Adult; Affect; Alcohol consumption; Alcohol dehydrogenase; Alcohol dependence; Alcohols; Animal Model; Animals; Award; Behavior; Behavioral; Biological Assay; Brain; Brain Diseases; Chromatin; Chronic; Complement; Consummatory Behavior; Consumption; Coupled; 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 (Brain); 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; Volition; Work; addiction; alcohol abuse therapy; alcohol effect; alcohol response; alcohol use disorder; base; behavioral response; binge drinking; career; clinically relevant; cost; defined contribution; drinking; drinking behavior; epigenetic regulation; epigenomics; extracellular; fomepizole; gene function; genetic manipulation; genome-wide; human model; in vivo; information processing; inhibitor/antagonist; innovation; knock-down; learned behavior; memory process; neurotransmission; new therapeutic target; novel; overexpression; peripheral blood; programs; recruit; relating to nervous system; 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 酒精成瘾是一个重大的公共卫生问题，需要付出巨大的财政和社会代价。 尽管如此，酒精成瘾仍然是一种难以治愈的疾病，缺乏常规药物治疗。 有效性和持久性。现有的许多关于神经生物学和酒精治疗的研究 成瘾集中在边缘奖赏回路，神经传递的变化，以及细胞内神经元的变化。 信号级联。然而，近年来，研究表观遗传作用的研究激增， 病理性酒精使用障碍的发展因素。基因表达的表观遗传学控制 在成人大脑中处理神经活动的关键作用，并且在人类和动物中有明确的证据 将大脑染色质的变化与成瘾联系起来的模型。近年来，染色质结合代谢酶 已经成为表观遗传调控的核心参与者，导致了遗传学模型的根本转变。 转录调控，并牵连表观遗传代谢过程中的分子和行为 对酒精的反应。这个NIH独立之路奖（K99/R 00）将大大促进 候选人的，博士Mews，有能力开始他的职业生涯作为一个独立的科学家，使他能够研究新的 酒精对这种代谢表观遗传基因调节的观点，并探索新的表观遗传因素 酒精使用障碍的治疗目标。在该补助金的辅导K阶段（具体目标1和具体目标2）， 目的2），将肝脏中的外周酒精代谢对脑中的组蛋白乙酰化的贡献 在啮齿类动物的饮酒相关的酗酒模型中测定。酒精诱导的组蛋白乙酰化 在海马体（与酒精成瘾密切相关的区域）进行局部和全局检测 脆弱性，以及源于肝脏的酒精衍生的乙酸盐对基因表达的直接调节 酒精代谢测试。此外，病毒操纵基因表达以操纵乙酰辅酶A 代谢将用于建立因果关系，并确定代谢-表观遗传ACSS 2途径是否 将酒精驱动的组蛋白乙酰化与消费增加和酒精相关学习联系起来。在 独立阶段（R 00），具体目标3，我们将结合这些联合收割机概念和技术创新 翻译狂饮模型的方法，以研究基于染色质的靶向机制 ACSS 2可以调节大脑中酒精诱导的特定基因表达。总之，研究 在这个独立之路奖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; 同时准备候选人与一套独特的智力和技术技能，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 神经表观遗传学和行为学的方法在技术上先进和高影响力的方式。