Epigenetic-metabolic aspects of alcohol use disorder and early developmental alcohol exposure

酒精使用障碍和早期发育酒精暴露的表观遗传代谢方面

• 批准号: 10327732
• 负责人: Gabor Egervari
• 金额: $ 14.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327732
• 关键词: Abstinence; Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Acetylation; Acute; Adult; Affect; Alcohol consumption; Alcohols; Amygdaloid structure; Animal Model; Behavior; Behavioral; Biological; Brain; Brain region; Cells; Chromatin; Cognition; Complex; Corpus striatum structure; DNA; Data; Deposition; Development; Developmental Gene; Disease; Dorsal; Enzymes; Epigenetic Process; Ethanol; Ethanol Metabolism; Etiology; Executive Dysfunction; Faculty; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Development; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genomics; Hippocampus (Brain); Histone Acetylation; Histones; Isotope Labeling; Knock-out; Knowledge; Label; Learning; Link; Mediating; Memory; Metabolic; Metabolism; Modeling; Mus; Nature; Neurobiology; Neurons; Neurophysiology - biologic function; Nuclear; Nuclear Translocation; Pathway interactions; Peripheral; Pharmacologic Substance; Pharmacology; Play; Positioning Attribute; Prefrontal Cortex; Pregnancy; Process; Property; Proteomics; Regulation; Relapse; Research; Rewards; Rodent Model; Role; Signal Transduction; Societies; Source; Structure; Techniques; Teratogens; Testing; Therapeutic; Time; Training; Ventral Striatum; Volition; Withdrawal; Work; addiction; alcohol effect; alcohol exposure; alcohol seeking behavior; alcohol testing; alcohol use disorder; binge drinking; brain dysfunction; career; classical conditioning; cofactor; craving; disease phenotype; efficacious treatment; epigenetic regulation; executive function; fetal; in utero; inhibitor; insight; mouse model; negative emotional state; novel; postnatal; prenatal; programs; skills; tenure track; therapeutic target; treatment strategy

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) continues to impose a tremendous burden on society and efficacious treatment options are severely lacking. Recently, epigenetic processes such as histone acetylation emerged as potential contributors to AUD. Acetylation of histones has been shown to facilitate DNA accessibility and gene expression. The dynamic and reversible nature of this process makes it a particularly promising potential therapeutic target. Novel evidence suggests that epigenetic regulation is dependent on metabolic state, implicating specific metabolic factors in neural functions that drive behavior (Li*, Egervari* et al, Nat Rev Mol Cell Biol 2018). Recently, our group has shown that neuronal histone acetylation is fueled by the metabolite acetyl-CoA that is produced from acetate by nuclear Acetyl-CoA Synthetase 2 (ACSS2; Mews et al, Nature 2017). As a major biological source of acetate is alcohol metabolism, I hypothesized that alcohol-derived acetate might have profound effects on the epigenetic landscape in the brain following binge drinking. Using heavy isotope labeling in mice, I showed that alcohol metabolism rapidly promotes histone acetylation in the brain by direct deposition of alcohol-derived acetyl groups onto histones in an ACSS2-dependent manner. I observed similar incorporation of alcohol-derived acetate into fetal brain, suggesting a potential role for ACSS2 during prenatal alcohol exposure. In adult mice, alcohol-induced histone acetylation led to increased expression of key neuronal genes linked to learning and memory. Strikingly, ACSS2 was required for ethanol-induced associative learning, which underlies craving and relapse after protracted periods of abstinence (Mews*, Egervari*# et al, Nature, 2019). These preliminary findings establish a direct and dynamic link between peripheral and central alcohol metabolism and brain histone acetylation with significant therapeutic potential. In this proposal, I will aim to (1) determine the importance of ACSS2 in voluntary alcohol intake and test whether ACSS2 inhibition decreases alcohol consumption in mice; (2) characterize the role of ACSS2 in prenatal alcohol exposure and in the development of fetal alcohol spectrum disorder; and (3) explore the potential relevance of this novel pathway in various brain regions that regulate different aspects of AUD. This study will make pioneering contributions to our understanding of alcohol’s effects on the brain with respect to epigenetic and metabolic processes, and has the potential to identify new pharmaceutical targets to ameliorate alcohol use disorder. In addition, the proposed training and research will greatly facilitate my transition to an independent tenured-track faculty position. I will learn a combination of computational, genomic and proteomic techniques and behavioral approaches that will help establish my niche and provide me with the skills necessary to work at the intersection of epigenetics, metabolism and alcohol neurobiology. With the acquisition of valuable skills that I describe in the training plan of this proposal, I will be in a unique position to reveal new insights into the role of epigenetic-metabolic regulation of brain function in the context of alcohol use.

项目总结/摘要 酒精使用障碍（AUD）继续给社会和有效治疗带来巨大负担 严重缺乏选择。最近，组蛋白乙酰化等表观遗传过程成为潜在的研究热点 贡献者AUD组蛋白的乙酰化已显示促进DNA可及性和基因表达。 该过程的动态和可逆性质使其成为特别有前途的潜在治疗靶点。 新的证据表明，表观遗传调控依赖于代谢状态，涉及特定的 驱动行为的神经功能中的代谢因子（Li*，Egervari* 等人，Nat Rev Mol Cell Biol 2018）。 最近，我们的研究小组已经表明，神经元组蛋白乙酰化是由代谢物乙酰辅酶A， 通过核乙酰辅酶A合成酶2从乙酸产生（ACSS 2; Mews等人，Nature 2017）。作为主要 醋酸盐的生物来源是酒精代谢，我假设酒精衍生的醋酸盐可能具有 对酗酒后大脑的表观遗传景观产生深远影响。使用重同位素标记 在小鼠中，我发现酒精代谢通过直接沉积迅速促进脑中组蛋白乙酰化 以ACSS 2依赖的方式将酒精衍生的乙酰基基团转移到组蛋白上。我观察到类似的合并 酒精衍生的乙酸盐进入胎儿大脑，表明ACSS 2在产前酒精中的潜在作用 exposure.在成年小鼠中，酒精诱导的组蛋白乙酰化导致关键神经元基因表达增加 与学习和记忆有关。引人注目的是，ACSS 2是乙醇诱导的联想学习所必需的， 是长期禁欲后渴望和复发的基础（Mews*，Egervari*# et al，Nature，2019）。 这些初步的发现建立了外周和中枢酒精代谢之间的直接和动态联系 和脑组蛋白乙酰化具有显著的治疗潜力。 在这项建议中，我的目标是（1）确定ACSS 2在自愿酒精摄入和测试中的重要性 ACSS 2抑制是否减少小鼠的酒精消耗;（2）表征ACSS 2在产前代谢中的作用。 酒精暴露和胎儿酒精谱系障碍的发展;（3）探索潜在的 这一新途径在调节AUD不同方面的各种大脑区域中的相关性。本研究将 为我们理解酒精对大脑的表观遗传影响做出了开创性的贡献。 和代谢过程，并有可能确定新的药物靶点，以改善酒精使用 disorder.此外，拟议的培训和研究将大大有助于我过渡到一个独立的 终身教职我将学习计算机、基因组学和蛋白质组学技术的结合 和行为方法，这将有助于建立我的利基，并为我提供必要的技能， 表观遗传学、新陈代谢和酒精神经生物学的交叉点。通过获得宝贵的技能， 在我所描述的这份培训计划建议中，我将在一个独特的位置上揭示新的见解作用 酒精使用背景下大脑功能的表观遗传代谢调节。