ACSS2 inhibition in treating Alcohol Abuse

ACSS2 抑制治疗酒精滥用

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

饮酒障碍代表了社会的巨大负担。而我们对神经元途径的理解成瘾中涉及的电路已经越来越多，可用治疗的功效没有看到相同成功。我们发现了一个控制神经元可塑性的新型表观遗传过程，这是长期的关键记忆形成，涉及代谢酶ACS21。 ACSS2生成乙酰辅酶A，这是一种关键辅助因子组蛋白乙酰化对长期记忆很重要2。我们发现ACSS2在通过协调酒精诱导的组蛋白乙酰化和基因表达与酒精相关的学习海马，通过将酒精来源的醋酸盐转化为乙酰辅酶A3。这个新证据进一步阐明乙醇如何通过依赖ACSS2依赖性组蛋白乙酰化促进其奖励性能。这从根本上新的基因调节机制提出了一种有吸引力的潜在治疗策略 ACS2的药理抑制以干扰与酒精相关的学习驾驶酒精使用障碍。在这个提案，我们将测试催化ACSS2（ACSS2I）的小分子抑制剂用于酒精的动物模型使用障碍（AUD）。提出的实验将验证并建立ACSS2I作为潜在的新型最终可以在心理治疗中最终使用的药物治疗来治疗酒精使用障碍。