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 的目标是了解环状 RNA (circRNA) 在机制中的作用可卡因重塑背侧纹状体（DS）和伏隔核（NAc）以引发强迫性可卡因- circRNA 是高度保守的单链“反向剪接”RNA，其中 5' 和 3' 新出现的证据表明，circRNA 是一类主要的转录本末端。大脑中富集的调节性非编码 RNA 在神经元的基本方面发挥着关键作用功能，但它们参与可卡因（和其他药物）的分子、细胞和行为作用滥用）尚未得到研究，我们将表征 DS 和 NAc 中的 circRNA 表达模式。使用双端核糖核酸测序显示出强迫性可卡因消耗的小鼠。我们还评估了患有可卡因使用障碍的人类死后纹状体组织中的 circRNA 表达。已经有强有力的证据表明可卡因对这些大脑区域中的几种 circRNA 具有显着的调节作用。那些在小鼠和人类中表现出类似异常表达的可卡因反应性 circRNA 将被我们将确定优先的可卡因反应性 circRNA 是否优先进行进一步研究。然后我们将研究不同类型的 DS 和 NAc 神经元中所发挥的作用。这些优先可卡因响应的 circRNA 调节可卡因的分子和细胞反应在 DS 和 NAc 的这些细胞类型中，这将通过使用体内 CRISPR 技术或 RNAi 来完成。以细胞类型特异性方式降低优先级 circRNA 并评估这些 circRNA 的影响控制基线和可卡因引起的神经元内在兴奋性的改变及其最后，我们将研究可卡因反应的方式。 circRNA 控制小鼠的强迫性可卡因自我给药行为，包括复发。创新研究有望对分子和细胞机制产生根本性的新见解可卡因成瘾，未来计划对阿片类药物滥用进行平行研究。