Circular RNA signaling in opioid seeking phenotypes

阿片类药物寻求表型中的环状 RNA 信号传导

基本信息

批准号：
10044727
负责人：
STEPHANIE Sillivan
金额：
$ 47.55万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10044727
关键词：
Abstinence Address Area Award Behavior Behavioral Binding Biogenesis Brain Brain region Chronic Chronic Disease Cognitive Data Set Disease Drug Exposure Enzymes Epigenetic Process Extinction (Psychology)Gene Expression Genetic Transcription Goals Heroin Light Messenger RNA MicroRNAs Modeling Molecular Molecular Biology Motivation Neurobiology Neurons Opioid Outcome Patients Pharmaceutical Preparations Phenotype Process Proteins Public Health RNA RNA Splicing Rattus Rehabilitation therapy Relapse Reporting Research Rewards Role Self Administration Signal Pathway Signal Transduction Substance Use Disorder Substance abuse problem Translations addiction behavioral phenotyping circular RNA cost drug seeking behavior genetic manipulation insight interdisciplinary approach novel opioid use disorder overdose death response targeted treatment

项目摘要

Abstract: Substance use disorder is a costly and debilitating chronic disorder, characterized by high rates of relapse despite successful attempts at rehabilitation and periods of abstinence. In addition, the rates of overdose and death associated with the opioid class of drugs have dramatically risen over the last decade and represent a major public health burden. To identify putative drug targets for the treatment of opioid use disorder, the molecular mechanisms that govern opioid seeking must be delineated. The goal of this proposal is to address this critical barrier in the field of substance abuse research by exploring entirely new mechanisms that modulate opioid seeking from a class of RNA called circular RNAs. Although circular RNAs have never been studied in drug seeking behaviors, this species of RNA has the potential to broadly influence cellular signaling at the epigenetic, transcriptional and translational levels, which in turn may impact a wide range of behavioral phenotypes. Circular RNAs are single-stranded transcriptional splice products that result from backsplicing of 3' to 5' ends of mRNA. Such splice products are beginning to be explored in the brain, with some expressed at higher levels than their mRNA counterparts, and have been reported to modulate critical processes including microRNA activity, gene expression, protein translation and even cognitive behaviors. We have identified a set of circular RNAs and their biogenesis enzymes that are regulated after heroin self-administration in the rat orbitofrontal cortex (OFC), a brain region essential to reward seeking. During the award period, we will explore the hypothesis that altered OFC circular RNA signaling contributes to opioid seeking phenotypes. We will use a multi-disciplinary approach to examine the cellular and behavioral consequences of heroin-induced circular RNA expression in a rat model of opioid seeking. First, heroin-associated circular RNAs will be genetically manipulated in the OFC to determine their contribution to motivation for opioids and relapse to opioid seeking after extinction or abstinence. We will then define the cellular phenotype of heroin-associated circular RNAs in the OFC for insights into the cellular circuits that have altered circRNA biogenesis as a result of heroin exposure. Finally, we will identify signaling pathways downstream of heroin-associated circular RNAs in the OFC to describe the molecular interactions of this novel class of RNA within drug-exposed neurons. Our dataset of heroin-associated circular RNAs have never been studied in the brain before and represent an entirely new area of research in the field of substance abuse. Therefore, the outcome of the unprecedented proposed studies will shed light on novel mechanisms that govern drug seeking and provide essential insight into the neurobiology of substance abuse.

抽象的：药物滥用障碍是一种昂贵且使人衰弱的慢性疾病，其特点是复发率高尽管成功地尝试了康复和禁欲期。此外，过量服用率和过去十年中，与阿片类药物相关的死亡急剧上升，代表了重大公共卫生负担。为了确定治疗阿片类药物使用障碍的假定药物靶标，必须描述控制阿片类药物寻求的分子机制。该提案的目标是解决通过探索全新的机制来克服药物滥用研究领域的关键障碍调节从一类称为环状 RNA 的 RNA 中寻找阿片类药物。尽管环状RNA从未被在药物寻找行为中进行研究，这种 RNA 具有广泛影响细胞信号传导的潜力在表观遗传、转录和翻译水平上，这反过来可能会影响广泛的行为表型。环状RNA是单链转录剪接产物，由RNA反向剪接产生 mRNA 的 3' 至 5' 末端。此类剪接产物已开始在大脑中进行探索，其中一些表达为其水平高于其 mRNA 对应物，据报道可以调节关键过程，包括 microRNA 活性、基因表达、蛋白质翻译甚至认知行为。我们已经确定了一组大鼠自我注射海洛因后受到调节的环状 RNA 及其生物发生酶眶额皮层（OFC），一个对于奖励寻求至关重要的大脑区域。颁奖期间，我们将探索 OFC 环状 RNA 信号传导的改变有助于阿片类药物寻求表型的假设。我们将使用一个多学科方法来检查海洛因引起的循环的细胞和行为后果阿片类药物寻求大鼠模型中的 RNA 表达。首先，海洛因相关的环状RNA将被遗传在 OFC 中进行操纵，以确定它们对阿片类药物动机和阿片类药物复发的贡献灭绝或禁欲后。然后我们将定义海洛因相关环状 RNA 的细胞表型 OFC 深入了解因海洛因而改变 circRNA 生物发生的细胞回路接触。最后，我们将确定海洛因相关环状 RNA 下游的信号通路 OFC 描述了暴露于药物的神经元内这类新型 RNA 的分子相互作用。我们的海洛因相关环状 RNA 数据集以前从未在大脑中进行过研究，代表了药物滥用领域的全新研究领域。因此，出现了史无前例的结果拟议的研究将揭示管理药物寻求的新机制并提供重要的见解进入药物滥用的神经生物学。