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

• 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
• 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

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.

项目概要 可卡因成瘾的特点是强迫性寻求药物和极易复发 因此，即使在长期禁欲之后，成瘾研究的一个主要焦点仍然是。 旨在识别大脑奖赏回路中发生的稳定的、可卡因诱导的神经适应。 众所周知，转录变化在禁欲期间持续存在，但潜在的分子机制 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（核受体亚家族 4） 我们的初步数据表明 Nr4a1 抑制可卡因奖赏和寻求行为。 可卡因诱导转录的中枢调节因子，包括晚期靶基因表达 治疗药物的使用加强了这项研究的意义。 调节 Nr4a1 并阻止小鼠可卡因自我给药，强调了巨大的 该基础研究计划在打击毒瘾方面的潜力。 鉴于组蛋白翻译后修饰 (hPTM) 会导致基因发生持久的变化 稳定细胞表型所必需的表达，在过程中获得的组蛋白修饰 禁欲可以解释个体基因如何“记住”之前的药物暴露。 先前发现 Nr4a1 在戒断后期调节单个靶基因的 hPTM。 该提案旨在定义细胞核中持续基因表达的机制 雄性和雌性小鼠自愿自我施用可卡因后的伏隔核（NAc）。 应用新方法对染色质和基因表达进行细胞类型特异性定量 然后，我们使用表观遗传学验证了 Nr4a1 作用的因果机制。 在本研究结束时，我们将定义细胞类型特异性。 Nr4a1 在可卡因戒除过程中调节稳定基因表达的机制。 为此，我们将应用机器学习来识别持久基因表达的新调节因子 与可卡因成瘾有关。