Epigenetic mechanisms of sustained transcription across cocaine abstinence

可卡因戒断过程中持续转录的表观遗传机制

基本信息

批准号：
10297955
负责人：
Elizabeth A Heller
金额：
$ 67.91万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297955
关键词：
Abstinence Attenuated Basic Science Behavior Behavioral Binding Bioinformatics Biology Brain CARTPT gene CRISPR interference Cell Differentiation process Cell Nucleus Chromatin Chronic Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Cocaine Dependence Data Data Set Development Drug Addiction Drug Exposure Drug Targeting Epigenetic Process Extinction (Psychology)Female Gene Activation Gene Expression Gene Expression Profiling Genes Genetic Transcription Histones Hour Individual Life Link Machine Learning Measures Mediating Mental Depression Mental disorders Methods Methyltransferase Modification Molecular Mus Nature Neurologic Neurons Nuclear Receptors Nucleus Accumbens Pathologic Pharmaceutical Preparations Pharmacology Phenotype Post-Translational Protein Processing Publishing Regulation Relapse Research Rewards Role Sampling Signal Transduction Substance Use Disorder Symptoms Testing Therapeutic Agents Volition Work addiction attenuation cell type cocaine exposure cocaine self-administration craving dopaminergic neuron drug abstinence epigenetic profiling experimental study genome-wide histone modification in vivo machine learning method male neuroadaptation new therapeutic target novel programs rat orphan nuclear receptor NR4A1 recruit small molecule transcription factor transcriptome sequencing unsupervised learning

项目摘要

PROJECT SUMMARY Cocaine addiction is characterized by compulsive drug seeking and high vulnerability to relapse even after prolonged abstinence. A major focus of the field of addiction research has therefore been to identify stable, cocaine-induced neuroadaptations occurring in brain reward circuits. Transcriptional changes are known to persist throughout abstinence, yet the underlying molecular mechanisms of such persistence remain elusive. We recently discovered that the transcription factor, Nr4a1 (nuclear receptor subfamily 4) represses cocaine reward and seeking behavior. Our preliminary data show that Nr4a1 is a central regulator of cocaine-induced transcription, including target gene expression in late abstinence. The significance of this study is strengthened by the utility of therapeutic agents that regulate Nr4a1 and block mouse cocaine self-administration, underscoring the enormous potential of this basic research program in combating drug addiction. Given that histone posttranslational modifications (hPTMs) confer long-lasting changes in gene expression necessary for stable cellular phenotypes, histone modifications acquired during abstinence may explain how individual genes “remember” prior drug exposure. We have previously found that Nr4a1 regulates hPTMs at individual target genes at late abstinence. This proposal aims to define the mechanism(s) of persistent gene expression in the nucleus accumbens (NAc) of male and female mice following volitional cocaine self-administration. We apply novel methods for cell-type specific quantification of both chromatin and gene expression in a single sample. We then validate the causal mechanism of Nr4a1 action using epigenetic editing in vivo. At the conclusion of this study we will have defined the cell-type specific mechanism by which Nr4a1 regulates stable gene expression across cocaine abstinence. Beyond this, we will apply machine learning to identify novel regulators of persistent gene expression relevant to cocaine addiction.

项目摘要可卡因成瘾的特征是强迫毒品寻求药物和易受救济的脆弱性即使在节制长期之后。因此，成瘾研究领域的重点是我们要确定脑奖励电路中发生的可卡因诱导的稳定的可卡因诱导的神经适应。已知转录变化始终在戒酒中持续存在，但是基本的分子这种持久性的机制仍然难以捉摸。我们最近发现转录因子NR4A1（核接收器亚家族4）压抑可卡因奖励和寻求行为。我们的初步数据表明NR4A1是一个可卡因诱导的转录的中央调节剂，包括近来的靶基因表达节制。这项研究的意义通过理论代理的实用性加强了调节NR4A1和阻止小鼠可卡因自我管理，强调了巨大的这项基础研究计划在打击药物成瘾方面的潜力。鉴于组蛋白翻译后修饰（HPTMS）会议的基因长期变化稳定的蜂窝表型所需的表达，在禁欲可能会解释单个基因如何“记住”先前的药物暴露。我们有先前发现NR4A1在戒酒后期调节单个靶基因的HPTM。这建议旨在定义核中持续基因表达的机制自愿可卡因自我管理后，雄性和雌性小鼠的伏伏人（NAC）。我们应用新颖的方法来对染色质和基因表达的细胞类型特异性定量在单个样本中。然后，我们使用表观遗传学验证NR4A1作用的因果机制体内编辑。在这项研究的结论中，我们将定义细胞类型的特异性 NR4A1调节可卡因戒酒的稳定基因表达的机制。超过这，我们将应用机器学习来识别持续基因表达的新型调节因子与可卡因成瘾有关。