ACSS2 inhibition in treating Alcohol Abuse

ACSS2 抑制治疗酒精滥用

• 批准号: 10546942
• 负责人: HOWARD C. BECKER
• 金额: $ 26万
• 依托单位: EPIVARIO, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546942
• 关键词: Acetates; Acetyl Coenzyme A; Address; Aftercare; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Attenuated; Automobile Driving; Behavior; Behavioral; Blood; Blood - brain barrier anatomy; Brain; Brain region; Calmodulin 1; Cause of Death; Cells; Cessation of life; Chromosome Mapping; Clinical Treatment; Corpus striatum structure; Data; Defect; Disease; Disulfiram; Dose; Drug Kinetics; Enzymes; Epigenetic Process; Ethanol; Exhibits; Exposure to; Extinction (Psychology); Family; Financial Hardship; Gene Chips; Gene Expression; Genes; Genetic Transcription; Grant; Half-Life; Healthcare Systems; Hippocampus (Brain); Histone Acetylation; Histones; Hour; In Vitro; Industry; Intake; Investigation; Knockout Mice; Lead; Learning; Legal patent; Link; Measures; Medical; Memory; Metabolic; Molecular; Monitor; Mus; N-Methylaspartate; Neuronal Plasticity; Neurons; Odors; Operant Conditioning; Oral; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Play; Procedures; Process; Property; Psychotherapy; Rattus; Regulator Genes; Relapse; Research; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Rivers; Rodent Model; Role; Safety; Self Administration; Small Business Innovation Research Grant; Societies; Stress; Substance Use Disorder; Testing; Therapeutic; Time; Training; Yohimbine; addiction; alcohol craving; alcohol cue; alcohol reward; alcohol use disorder; cofactor; consumption measures; cost; craving; druggable target; effective therapy; efficacy testing; experimental study; genome-wide; improved; inhibitor; innovation; knock-down; knockout animal; long term memory; memory consolidation; mouse model; novel; pre-clinical; prevent; psychologic; side effect; small hairpin RNA; small molecule inhibitor; social; stressor; success; treatment duration

Alcohol use disorder represents a tremendous burden on society. While our understanding of neuronal pathways and circuitry involved in addiction has grown of late, efficacy of available treatments has not seen the same success. We uncovered a novel epigenetic process controlling neuronal plasticity that is key to long-term memory formation, involving the metabolic enzyme ACSS21. ACSS2 generates acetyl-CoA, a key cofactor for histone acetylation that is important for long-term memory2. We discovered that ACSS2 plays a critical role in alcohol-related learning by coordinating alcohol-induced histone acetylation and gene expression in the hippocampus, through conversion of alcohol-derived acetate to acetyl-CoA3. This new evidence further elucidates how ethanol may facilitate its rewarding properties via ACSS2-dependent histone acetylation. This radically new gene regulatory mechanism presents an attractive potential therapeutic strategy via pharmacological inhibition of ACSS2 to interfere with alcohol-related learning driving alcohol use disorder. In this proposal, we will test small molecule inhibitors of catalytic ACSS2 (ACSS2i) for use in animal models of alcohol use disorder (AUD). The proposed experiments will validate and establish ACSS2i as potential novel pharmacotherapies that may ultimately be used in the context of psychotherapy to treat alcohol use disorder.

酒精使用障碍是社会的巨大负担。虽然我们对神经通路的理解 和涉及成瘾的电路最近已经增长，可用的治疗方法的疗效并没有看到相同的 成功我们发现了一种新的控制神经元可塑性的表观遗传过程，这是长期的关键。 记忆的形成，涉及代谢酶ACSS 21。ACSS2产生乙酰辅酶A，乙酰辅酶A是ACSS2的关键辅因子。 组蛋白乙酰化对长期记忆很重要。我们发现ACSS 2在以下方面发挥着关键作用 通过协调酒精诱导的组蛋白乙酰化和基因表达， 海马，通过转化酒精衍生的乙酸乙酰辅酶A3。这一新证据进一步 阐明了乙醇如何通过ACSS2依赖性组蛋白乙酰化促进其有益特性。这 一种全新的基因调控机制， 药理学抑制ACSS2以干扰酒精相关的学习驾驶酒精使用障碍。在这 我们将测试催化ACSS 2（ACSS 2i）的小分子抑制剂，用于酒精的动物模型 使用障碍（AUD）。所提出的实验将验证和确立ACSS 2i作为潜在的新颖的 这些药物疗法最终可能在心理治疗的背景下用于治疗酒精使用障碍。