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: 10228756
• 负责人: Philipp Mews
• 金额: $ 15.36万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228756
• 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 对酒精的成瘾是一个重大的财务和社会成本的重大公共卫生问题。 尽管如此，酒精成瘾仍然是一种顽固疾病，缺乏常规的药物治疗 实质性耐用的效率。关于神经生物学和酒精治疗的现有研究 成瘾重点是边缘奖励电路，神经传递的变化和细胞内神经元 信号级联。但是，近年来，研究表观遗传学的作用激增 病理饮酒障碍发展的因素。基因表达的表观遗传控制作用 在处理成人大脑的神经活动中的关键作用，人类和动物有明确的证据 将大脑染色质变化与成瘾联系起来的模型。近年来，结合染色质的代谢酶 已经成为表观遗传调节的中心参与者，导致了模型的基本转变 转录调控以及分子和行为中隐式表观遗传代谢过程 对酒精的反应。这项NIH独立奖（K99/R00）将大大支持 候选人的Mews博士，能够开始他的独立科学家职业，允许他学习新 通过酒精调节这种代谢性基因的观点，并探索表观遗传因素作为新颖 酒精使用障碍的治疗靶标。在这笔赠款的物质K期中（特定目的1和特定 AIM 2），肝脏外周酒精代谢对大脑组蛋白乙酰化的贡献将是 在啮齿动物中的翻译相关的暴饮暴食模型中确定。酒精诱导的组蛋白乙酰化将 在海马中分配本地和全球，一个与酒精成瘾密切相关的地区 脆弱性，以及源自肝的酒精衍生的醋酸盐对基因表达的直接调节 酒精代谢将进行测试。此外，病毒操纵基因表达以操纵乙酰辅酶A 代谢将用于建立因果关系，并确定代谢性ACSS2途径是否 将酒精驱动的组蛋白乙酰化与增加的消费和与酒精有关的学习联系起来。在 独立阶段（R00），特定的目标3，我们将在概念和技术上创新地结合这些这些 使用翻译的暴饮暴食模型来研究基于染色质的靶向机制 这允许ACSS2调节酒精在大脑中诱导的特定基因表达。总而言之 在这一获得独立奖的途径中提出的将阐明代谢性机制 酒精会影响神经元过程以及与酒精有关的学习和饮酒行为；尽管 同样，用独特的智力和技术技能来准备候选人，这将使他 制定一项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的方式进行神经验证和行为方法。

项目成果

Shared and divergent transcriptomic regulation in nucleus accumbens D1 and D2 medium spiny neurons by cocaine and morphine.

可卡因和吗啡对伏隔核 D1 和 D2 中棘神经元的共享和不同的转录组调节。

• DOI: 10.1101/2023.09.19.558477
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Browne,CalebJ;Mews,Philipp;Zhou,Xianxiao;Holt,LeanneM;Estill,Molly;Futamura,Rita;Schaefer,Anne;Kenny,PaulJ;Hurd,YasminL;Shen,Li;Zhang,Bin;Nestler,EricJ
• 通讯作者: Nestler,EricJ

Convergent abnormalities in striatal gene networks in human cocaine use disorder and mouse cocaine administration models.

• DOI: 10.1126/sciadv.add8946
• 发表时间: 2023-02-10
• 期刊: Science advances
• 影响因子: 13.6