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: 10745787
• 负责人: Gabor Egervari
• 金额: $ 24.85万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-05 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745787
• 关键词: Abstinence; Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Acetylation; Acute; Adult; Affect; Alcohol consumption; Alcohols; Amygdaloid structure; Animal Model; Association Learning; Behavior; Behavioral; Biological; Brain; Brain region; Cells; Chromatin; Cognition; Complex; Corpus striatum structure; Cues; 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; Histone Acetylation; Histones; Human; Isotope Labeling; Knock-out; Knowledge; Label; Learning; Link; Mediating; Memory; Metabolic; Metabolism; Modeling; Mus; Nature; Neurobiology; Neuronal Differentiation; Neurons; Neurophysiology - biologic function; Nuclear; Nuclear Translocation; Pathway interactions; Peripheral; Pharmacologic Substance; 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; Withdrawal; Work; addiction; alcohol effect; alcohol exposure; alcohol seeking behavior; alcohol testing; alcohol use disorder; binge drinking; brain dysfunction; career; cofactor; craving; disease phenotype; efficacious treatment; epigenetic regulation; executive function; fetal; histone acetyltransferase; in utero; inhibitor; insight; mouse model; negative emotional state; novel; pharmacologic; 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.

项目摘要/摘要 酒精使用障碍（AUD）继续对社会施加巨大的伯宁和有效的治疗 选项严重缺乏。最近，表观遗传过程（例如组蛋白乙酰化）作为潜力出现 AUD的贡献者。组蛋白的乙酰化已被证明可促进DNA的可及性和基因表达。 该过程的动态和可逆性使其成为一个特别有希望的潜在治疗靶点。 新的证据表明，表观遗传调节取决于代谢状态，暗示特定 驱动行为的神经功能中的代谢因子（Li*，Egervari*等，Nat Rev Mol Cell Biol 2018）。 最近，我们的小组表明，神经元组蛋白乙酰化是由代谢产物乙酰辅酶A助长的 由核乙酰辅酶A合成酶2（ACSS2; Mews等人，自然，2017年）产生。作为专业 乙酸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 暴饮暴食后，对大脑表观遗传景观的深远影响。使用重型同位素标记 在小鼠中，我表明酒精代谢通过直接沉积迅速促进大脑中的组蛋白乙酰化 以ACSS2依赖性方式进入组蛋白的乙酰乙酰基。我观察到类似的工作 酒精衍生的醋酸盐进入胎儿大脑，表明ACSS2在产前酒精期间的潜在作用 接触。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的表达增加 与学习和记忆有关。令人惊讶的是，乙醇引起的联想学习需要ACSS2，这是 渴望的渴望和继电器是旷日持久的渴望和继电器（Mews*，Egervari*＃et al，Nature，2019年）。 这些初步发现在外围和中央酒精代谢之间建立了直接而动态的联系 和脑组蛋白乙酰化具有明显的治疗潜力。 在此提案中，我的目标是（1）确定ACSS2在自愿饮酒和测试中的重要性 ACSS2抑制是否会减少小鼠的饮酒； （2）表征ACSS2在产前的作用 酒精暴露和胎儿酒精谱系障碍的发展； （3）探索潜力 在调节AUD不同方面的各个大脑区域，这种新型途径的相关性。这项研究会 为我们对酒精对大脑的影响的表观遗传的影响做出开创性的贡献 和代谢过程，并有可能识别新的药物靶标以减轻酒精的使用 紊乱。此外，拟议的培训和研究将极大地支持我向独立的过渡 终身轨道教师职位。我将学习计算，基因组和蛋白质组学技术的组合 和行为方法将有助于建立我的利基市场，并为我提供工作所需的技能 表观遗传学，代谢和酒精神经生物学的交集。通过获得宝贵技能 我在该提案的培训计划中描述，我将处于独特的位置，以揭示有关该角色的新见解 在饮酒的背景下，脑功能的表观遗传代谢调节。