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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要酒精成瘾是一个重大的公共卫生问题，造成巨大的经济和社会成本。尽管如此，酒精成瘾仍然是一种顽固性疾病，缺乏传统的药物疗法许多现有的神经生物学和酒精治疗研究都具有实质性和持久的功效。成瘾主要集中在边缘奖励回路、神经传递的变化和细胞内神经元然而，近年来，研究表观遗传学作用的研究激增。基因表达的表观遗传控制在病理性酒精使用障碍的发展中发挥着重要作用。在处理成人大脑的神经活动中发挥着关键作用，并且在人类和动物中都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，染色质结合的代谢酶。已成为表观遗传调控的核心参与者，导致模型发生根本性转变转录调控，并涉及分子和行为中的表观遗传代谢过程 NIH 独立之路奖 (K99/R00) 将极大地促进对酒精的反应。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代谢表观遗传基因的调控的观点，并探索表观遗传因素作为新的在本次资助的指导 K 阶段中，酒精使用障碍的治疗目标（具体目标 1 和具体目标）。目标 2)，肝脏中外周酒精代谢对大脑中组蛋白乙酰化的贡献将是在啮齿类动物的翻译相关的暴饮暴食模型中确定了酒精诱导的组蛋白乙酰化。在海马体中进行局部和全球检测，该区域与酒精成瘾密切相关脆弱性，以及源自肝脏的酒精衍生的乙酸盐对基因表达的直接调节此外，还将测试病毒对基因表达的操纵以操纵乙酰辅酶A。代谢将用于建立因果关系并确定代谢-表观遗传 ACSS2 途径是否将酒精驱动的组蛋白乙酰化与增加的消费和酒精相关的学习联系起来。独立阶段（R00），具体目标3，我们将结合这些概念和技术创新使用转化暴饮模型的方法来研究基于染色质的靶向机制总而言之，该研究允许 ACSS2 调节大脑中酒精诱导的特定基因表达。该独立之路奖中提出的建议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；同时为候选人准备一套独特的智力和技术技能，使他能够制定一个完全独立的酒精成瘾研究计划，能够整合广泛的以技术先进和高影响力的方式研究神经表观遗传学和行为方法。