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

基本信息

批准号：
8436138
负责人：
KRISTINE M. WIREN
金额：
$ 31.66万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8436138
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 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

项目摘要

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）：遗传和环境贡献在复杂疾病（例如酒精中毒）的发展中都具有至关重要的作用。不幸的是，在戒酒期间确定改变的基本分子机制以帮助开发新型治疗剂以维持清醒的情况下，几乎没有取得进展。我们提出了一种遗传，分子，药理和行为策略的组合，以识别禁酒时期后改变的途径。大脑结构，可塑性和基因表达中的神经适应于慢性酒精滥用，但这些表达差异在戒酒中的稳定性是有争议的。我们先前已经报道了在定义的禁欲期间，前额叶皮层（PFC）改变了与认知功能障碍和酗酒者损害相关的大脑区域改变的途径。为了表征遗传贡献，分析了对通过选择性繁殖得出的对酒精反应的动物模型的性别，抗戒断性癫痫发作（WSR）和戒断癫痫发作（WSP）线（WSP）线。在禁欲的持续时期，转录反应与戒断表型而不是性别相关。生物信息学分析表明，在WSR和WSP小鼠之间最大的二态性的主要途径中，“乙酰化”和“组蛋白脱乙酰基酶复合物”。数据显示了在禁欲期间的复杂表型特异性调节，表明在低反应WSR中广泛表观遗传重编程，但没有暴露于相同乙醇浓度的高反应WSP小鼠。我们将通过整合来自高通量靶向技术的数据，包括表达分析，DNASEI-SEQ和CHIP-SEQ，并确认我们在我们既定的依赖性相对诱导的相对诱导的相对诱导的相对诱导的相对诱导的相对诱导的途径中调节途径的参与，并确认在三个特定目标中确定表型特异性的调节机制，包括表达分析，DNAsei-Seq和Chip-Seq，包括表达分析，DNAsei-SEQ和CHIP-SEQ。我们假设可靶向的表观遗传机制在节制期间保持表达差异，并且这些差异会增加对酒精内表型低反应的复发风险。这些研究的影响很大，因为与酒精滥用相关的发病率/死亡率，一般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，神经适应性的变化和改变的表达模式也可能在禁欲期间对持续的神经毒性和脑损伤发挥作用，对学习和记忆功能有害后果，以在成瘾的下降周期和酗酒的自我维持性质中发挥作用。因此，这些目标的成功完成将有助于我们理解复发风险的基本机制，并提高我们通过鉴定新的药物治疗剂或增强对当前可用疗法的转化应用，并提高针对低反应内表型的酒精滥用疗法的能力。