Epitranscriptomic Regulation of Synaptic Responses to Drugs of Abuse

对滥用药物的突触反应的表观转录调控

• 批准号: 10433956
• 负责人: Kathryn D Meyer
• 金额: $ 47.74万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433956
• 关键词: Adenosine; Behavior; Behavioral; Binding; Binding Proteins; Brain; Chemicals; Chronic; Cocaine; Complex; Drug Exposure; Electrophysiology (science); Epigenetic Process; Event; Exposure to; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Genome; Mediating; Messenger RNA; Methylation; Modification; Molecular; Mus; Pathway interactions; Pharmaceutical Preparations; Production; Proteins; RNA; Regulation; Role; Synapses; Synaptic Potentials; Synaptic plasticity; addiction; cocaine exposure; drug of abuse; epitranscriptome; epitranscriptomics; experimental study; human disease; improved; in vivo; methylome; neuroadaptation; new therapeutic target; novel; response; tool; transcriptome

ABSTRACT Chronic exposure to drugs of abuse leads to persistent changes in synaptic connectivity which underlie the complex behaviors that characterize addiction. Thus, uncovering the factors that regulate synaptic plasticity is critical for understanding the molecular underpinnings of drug-induced neural adaptation and improving our ability to treat addiction. Several studies to date have focused on epigenetic mechanisms of gene expression that regulate the genome, whereas modifications to the transcriptome have been largely overlooked. Methylation of adenosine residues (m6A) has recently been shown to be a widespread RNA modification found in thousands of cellular mRNAs. Furthermore, m6A is particularly abundant within the brain, and its regulation has been implicated in the behavioral and electrophysiological response to cocaine. Recent studies have begun to reveal that m6A regulates gene expression changes during synaptic activity. However, whether m6A contributes to synaptic changes in gene expression that underlie drug-induced plasticity remains unknown. Here, we will explore the novel hypothesis that m6A-mediated changes in local protein production at the synapse regulate gene expression changes caused by drugs of abuse. First, we will identify cocaine-induced changes to the local methylome within the mouse brain and identify potential synaptic mRNAs which are regulated through mRNA methylation. Second, we will develop novel tools for the in vivo identification of transient m6A:protein interactions to identify both new m6A binding proteins as well as dynamic m6A binding events induced by cocaine exposure. Third, we will use a combination of global gene expression profiling and gene targeting approaches to determine how m6A regulates local gene expression following cocaine exposure. Collectively, these studies will explore novel roles of the epitranscriptome in controlling drug-induced gene expression changes and will likely reveal new mechanisms that regulate long-term synaptic changes that occur during addiction.

抽象的 长期接触滥用药物会导致突触连通性的持续变化，这是 表征成瘾的复杂行为。因此，发现调节突触可塑性的因素是 了解药物诱导的神经适应和改善我们的分子基础至关重要 治疗成瘾的能力。迄今为止的几项研究集中在基因表达的表观遗传机制上 调节基因组，而对转录组的修改很大程度上被忽略了。甲基化 腺苷残基（M6A）最近已被证明是数千个中广泛的RNA修饰 细胞mRNA。此外，M6A在大脑中特别丰富，其调节一直是 与对可卡因的行为和电生理反应有关。最近的研究开始揭示 该M6A调节基因表达在突触活性过程中的变化。但是，M6A是否有助于 基因表达的突触变化是药物诱导的可塑性基础仍然未知。在这里，我们会的 探索新的假设，即M6A介导的突触调节基因的局部蛋白质产生的变化 滥用药物引起的表达变化。首先，我们将确定可卡因引起的局部变化 小鼠大脑内的甲基团并鉴定通过mRNA调节的潜在突触mRNA 甲基化。其次，我们将开发用于瞬态M6A体内识别的新型工具：蛋白质 相互作用以识别新的M6A结合蛋白以及可卡因诱导的动态M6A结合事件 接触。第三，我们将结合全球基因表达分析和基因靶向方法 确定可卡因暴露后M6A如何调节局部基因表达。这些研究总的来说 探索表参数组在控制药物诱导的基因表达变化中的新作用，可能会 揭示了调节成瘾过程中长期突触变化的新机制。