Role for Circular RNAs in Compulsive Cocaine Intake

环状 RNA 在强迫性可卡因摄入中的作用

基本信息

批准号：
10062505
负责人：
Paul J. Kenny
金额：
$ 24.09万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062505
关键词：
Abstinence Autopsy Aversive Stimulus Awareness Back Behavior Behavioral Biological Assay Biological Process Brain Brain region CRISPR/Cas technology Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Cocaine Dependence Collaborations Complement Consumption Corpus striatum structure Data Development Disease Dopamine D1 Receptor Dorsal Dose Drug Addiction Etiology Functional disorder Future Genes Genetic Transcription Goals Habits Human In Situ Hybridization Intake Investigation Laboratories Laboratory Animals Mammalian Cell Mediating Methods MicroRNAs Molecular Motivation Mus Nature Neurobiology Neuroglia Neuronal Plasticity Neurons Nucleus Accumbens Pattern Pharmaceutical Preparations Play Population Program Research Project Grants Property Proteins Public Health RNA RNA Interference RNA Splicing Regulation Relapse Role Self Administration Site Slice Substance Use Disorder Synapses Synaptic Transmission Transcript Transcriptional Regulation Untranslated RNA Volition Whole-Cell Recordings Work addiction cell type circular RNA cocaine self-administration cocaine use drug of abuse human subject human tissue in vivo innovation insight knock-down mouse model novel opioid abuse response reward circuitry transcriptome sequencing transcriptomics virtual

项目摘要

PROJECT SUMMARY/ABSTRACT– PROJECT 2 Project 2's objective is to understand the role for circular RNAs (circRNAs) in the mechanisms by which cocaine remodels the dorsal striatum (DS) and nucleus accumbens (NAc) to precipitate compulsive cocaine- seeking behaviors. circRNAs are highly conserved single-stranded ‘back-spliced’ RNAs in which the 5′ and 3′ ends of the transcript are covalently joined. Emerging evidence suggests that circRNAs are a major class of regulatory noncoding RNAs that are enriched in brain and that play key roles in basic aspects of neuronal function, but their involvement in the molecular, cellular, and behavioral actions of cocaine (and other drugs of abuse) has yet not been investigated. We will characterize patterns of circRNA expression in DS and NAc of mice that show compulsive-like cocaine consumption using paired-end ribominus RNA-sequencing. We will also assess circRNA expression in postmortem striatal tissues from humans with cocaine use disorders. We already have robust evidence for prominent cocaine regulation of several circRNAs in these brain regions. Those cocaine-responsive circRNAs that show similar abnormal expression in mice and humans will be prioritized for further investigation. We will determine whether prioritized cocaine-responsive circRNAs are regulated specifically in different types of DS and NAc neurons. We will then investigate the role played by these prioritized cocaine-responsive circRNAs in regulating the molecular and cellular responses to cocaine within these cell types of DS and NAc. This will be accomplished by use of in vivo CRISPR technology or RNAi to knockdown prioritized circRNAs in a cell type-specific manner and assess the influence of these circrRNAs in controlling baseline and cocaine-induced alterations in the intrinsic excitability of the neurons as well as their transcriptional responses to cocaine. Finally, we will investigate the ways in which cocaine-responsive circRNAs control compulsive-like cocaine self-administration behavior including relapse in mice. These highly innovative studies promise to yield fundamentally new insights into the molecular and cellular mechanisms of cocaine addiction, with parallel future studies planned for opiate drugs of abuse.

项目摘要/摘要 - 项目2 项目2的目标是了解循环RNA（CIRCRNA）的作用可卡因重塑背纹状体（DS）和伏隔核（NAC），以沉淀强迫可卡因 - 寻求行为。 circrnas是高度保守的单链“后spled” RNA，其中5'和3' 成绩单的末端共价连接。新兴的证据表明，circrnas是富含大脑的调节性非编码RNA，并且在神经元的基本方面起关键作用功能，但它们参与可卡因的分子，细胞和行为作用（以及其他药物虐待）尚未进行调查。我们将表征在DS和NAC中表达的模式使用成对的末端Ribominus RNA测序显示出强迫性可卡因消耗的小鼠。我们将还要评估来自患有可卡因使用障碍的人类的术后纹状体组织中的ciRCRNA表达。我们在这些大脑区域中，对几种CircrNA的明显可卡因调节已经有强有力的证据。那些在小鼠和人类中表现出相似异常表达的可卡因反应性circrnas将是优先进行进一步研究。我们将确定优先级可卡因响应性circrnas是在不同类型的DS和NAC神经元中专门调节。然后，我们将调查由这些优先的可卡因响应性circrnas在调节可卡因的分子和细胞反应中在这些细胞类型中，DS和NAC。这将通过使用体内CRISPR技术或RNAi来实现以细胞类型特异性的方式敲除优先级CIRCRNA并评估这些circrrnas 在控制基线和可卡因引起的神经元及其内在刺激性的改变时对可卡因的转录反应。最后，我们将研究可卡因响应性的方式 CIRCRNA控制强迫性可卡因自我给药行为，包括小鼠中继。这些很高创新研究有望从根本上对分子和细胞机制产生新的见解可卡因成瘾，计划未来的研究计划，以优化滥用药物。