Epigenetics underlies long-term risk of relapse during abstinence

表观遗传学是戒烟期间复发长期风险的基础

• 批准号: 8601151
• 负责人: KRISTINE M. WIREN
• 金额: $ 30.13万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601151
• 关键词: Abstinence; Acetylation; Alcohol Phenotype; Alcohol Withdrawal Seizures; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcoholism; Animal Model; Behavioral; Binding Sites; Bioinformatics; Brain; Brain Injuries; Brain region; Breeding; Cause of Death; ChIP-seq; Chromatin; Chromatin Structure; Chronic; Complex; DNA; Data; Data Analyses; Dependence; Development; Disease; Enzymes; Epigenetic Process; Ethanol; Gene Expression; General Population; Genes; Genetic; Genome; Genotype; Health; Histone Deacetylase; Histone H3; Histones; Human; Hypersensitivity; Impaired cognition; Incidence; Intervention; Intoxication; Learning; Lysine; Maintenance; Maps; Massive Parallel Sequencing; Medial; Memory; Methyltransferase; Microinjections; Modeling; Modification; Molecular; Molecular Genetics; Molecular Profiling; Morbidity - disease rate; Mus; Nature; Pathway interactions; Pattern; Pharmacotherapy; Phenotype; Plastics; Play; Prefrontal Cortex; Proteins; Public Health; Regulation; Relapse; Reporting; Resistance; Risk; Role; Seizures; Severities; Staging; Structure; Technology; Therapeutic; Tissues; United States; Validation; Withdrawal; addiction; alcohol abuse therapy; alcohol exposure; alcohol response; alcohol use disorder; chromatin immunoprecipitation; craving; drinking; endophenotype; in vivo; inhibitor/antagonist; mortality; mouse model; neuroadaptation; neurotoxicity; next generation sequencing; novel; novel therapeutics; pressure; problem drinker; public health relevance; response; sex; sobriety; therapeutic target; ward

DESCRIPTION (provided by applicant): Both genetic and environmental contributions have crucial roles in the development of a complex disease such as alcoholism. Unfortunately, little progress has been made in identifying the underlying molecular mechanisms altered during abstinence to aid development of novel therapeutics for the maintenance of sobriety. We propose a combined genetic, molecular, pharmacological and behavioral strategy to identify pathways that are altered after a period of abstinence. Neuroadaptations in brain structure, plasticity and gene expression occur with chronic alcohol abuse, but the stability of these expression differences in the abstinent alcoholic is controversial. We have previously reported identification of pathways altered in prefrontal cortex (PFC), a brain region associated with cognitive dysfunction and damage in alcoholics, during a defined period of abstinence. To characterize genetic contributions, both sexes of an animal model with widely divergent responses to alcohol derived by selective breeding, the Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) lines, were analyzed. During a sustained period of abstinence, the transcriptional response correlated with withdrawal phenotype rather than sex. Bioinformatic analysis showed that among the major pathways altered that were the most dimorphic between WSR and WSP mice were 'acetylation' and 'histone deacetylase complex'. Data shows a complex phenotype-specific regulation during abstinence indicating widespread epigenetic reprogramming in the low response WSR but not the high response WSP mice exposed to the same ethanol concentrations. We will identify phenotype-specific regulatory mechanisms in the low response animal model in three specific aims by integrating data from high-throughput targeting technologies including expression profiling, DNaseI-seq and ChIP-seq, with confirmation of involvement of pathways to modulate relapse using pharmacological intervention in our established dependence-induced relapse drinking model. We hypothesize that targetable epigenetic mechanisms maintain expression differences during abstinence and that these differences increase the risk of relapse in the low response to alcohol endophenotype. These studies have high impact because of the morbidity/mortality associated with alcohol abuse, the high incidence of alcohol use disorders in the general population, and the tremendous impact these maladies have on human health. In addition, neuroadaptive changes and altered expression patterns may also play a role in persistent neurotoxicity and brain damage during abstinence with detrimental consequences for learning and memory functions, to play a role in the down-ward cycle of addiction and the self-sustaining nature of alcoholism. Thus, successful completion of these aims will aid in our understanding of the mechanism(s) underlying the risk for relapse and advance our ability to provide therapy for alcohol abuse targeted to the low response endophenotype, through identification of novel pharmacotherapies or to enhance translational applications for currently available therapeutics with previously unrecognized utility.

描述（由申请人提供）：遗传和环境因素在酒精中毒等复杂疾病的发展中都起着至关重要的作用。不幸的是，在确定禁欲期间改变的潜在分子机制以帮助开发维持清醒的新疗法方面进展甚微。我们提出了一种结合遗传、分子、药理学和行为的策略来识别禁欲一段时间后改变的途径。长期酗酒会导致大脑结构、可塑性和基因表达的神经适应，但戒酒者中这些表达差异的稳定性存在争议。我们之前曾报道过，在规定的戒酒期间，前额皮质（PFC）中的通路发生了改变，前额皮质是与认知功能障碍和酗酒者损伤相关的大脑区域。为了表征遗传贡献，对通过选择性育种产生的对酒精反应差异很大的动物模型的两性，即抗戒断性癫痫发作（WSR）和易发生戒断性癫痫发作（WSP）品系进行了分析。在持续的禁欲期间，转录反应与戒断表型相关，而不是与性别相关。生物信息学分析表明，WSR 和 WSP 小鼠之间最具二态性的主要改变途径是“乙酰化”和“组蛋白脱乙酰酶复合物”。数据显示，禁欲期间存在复杂的表型特异性调节，表明在低反应 WSR 小鼠中存在广泛的表观遗传重编程，但在暴露于相同乙醇浓度的高反应 WSP 小鼠中则不然。我们将通过整合来自高通量靶向技术（包括表达谱、DNaseI-seq 和 ChIP-seq）的数据，确定低反应动物模型中三个特定目标的表型特异性调节机制，并确认在我们建立的依赖诱导复发饮酒模型中使用药物干预来调节复发的途径。我们假设可靶向的表观遗传机制在戒酒期间维持表达差异，并且这些差异增加了对酒精内表型低反应的复发风险。这些研究具有很高的影响力，因为与酒精滥用相关的发病率/死亡率、普通人群中酒精使用障碍的高发病率以及这些疾病对人类健康的巨大影响。此外，神经适应性变化和表达模式的改变也可能在戒酒期间的持续神经毒性和脑损伤中发挥作用，对学习和记忆功能产生不利影响，从而在成瘾的下行循环和酗酒的自我维持性质中发挥作用。因此，成功完成这些目标将有助于我们理解复发风险背后的机制，并通过识别新的药物疗法或增强目前可用的具有先前未被认识的效用的疗法的转化应用，提高我们针对低反应内表型提供针对酒精滥用的治疗的能力。