COCA: Project 1. Drug-induced ROS and Epigenetic Mechanisms

COCA：项目 1. 药物诱导的 ROS 和表观遗传机制

基本信息

批准号：
10630228
负责人：
Christopher W Cowan
金额：
$ 27.38万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2019-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10630228
关键词：
Abstinence Acetylcysteine Animals Antioxidants Behavior Binding Biological Brain C-terminal Cells ChIP-seq Chronic Cocaine Cocaine Dependence Complex Corpus striatum structure Cues Cysteine Data Development Drug Addiction Drug Stability Drug usage Enzymes Epigenetic Process Event Exclusion Gene Expression Gene Expression Regulation Generations Genes Genomics Glutathione Goals HDAC4 gene HDAC5 gene Heroin Histone Deacetylase Human Mediating Memory Modification Molecular Molecular Genetics Mus Neurons Nitrogen Nuclear Nuclear Export Nucleus Accumbens Opiate Addiction Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Oxygen Pharmaceutical Preparations Phosphorylation Phosphorylation Site Post-Translational Protein Processing Protein Dephosphorylation Proteins Rattus Regulation Relapse Role Self Administration Signal Induction Signal Transduction Signaling Protein Site Specificity Structure Sulfhydryl Compounds Testing Therapeutic Time Training Validation Viral addiction cell type chromatin remodeling cocaine relapse cocaine seeking cocaine self-administration disulfide bond drug of abuse drug reward drug seeking behavior genetic approach heroin use mouse genetics mutant new therapeutic target novel stress reduction synergism tool transcriptome sequencing treatment strategy

项目摘要

PROJECT SUMMARY – Project 1 Cowan A major challenge for treating drug addiction is the poor understanding of the molecular mechanisms by which drug use produces persistent changes in brain function that facilitate drug seeking even after long periods of abstinence. Chronic drug use engages an epigenetic process, involving the chromatin-remodeling enzyme, histone deacetylase 5 (HDAC5), in striatal medium spiny neurons that functions to limit the development of multiple addiction-related behaviors, including reinstatement of cocaine and heroin seeking. However, HDAC5’s regulation and function during and after drug taking is complex and poorly understood. Cocaine and heroin produce reactive oxygen and nitrogen species (ROS/RNS) that alter the redox state of the cell, and redox-mediated cysteine thiol modifications alter the structure/function of target proteins, including class IIa HDACs. Repeated treatment of animals or humans with the antioxidant and glutathione precursor, N- acetylcysteine (NAC), reduces the vulnerability to reinstatement of cocaine and heroin seeking, and NAC blocks ROS-promoted HDAC5 nuclear export. The long-term goal of Project 1 is to understand the redox protein signaling and epigenetic mechanisms by which HDAC5 and NAC regulate heroin and cocaine relapse behaviors in hopes of identifying better therapeutic strategies for the treatment of drug addiction. We hypothesize that: (1) cocaine- and heroin-produced oxidative stress modifies HDAC5 cysteine thiol groups in the nucleus accumbens, which promotes nuclear export and reduces the anti-relapse actions of HDAC5, and (2) the anti-relapse effects of repeated NAC treatment are due, at least in part, to its ability to protect HDAC5 from ROS signaling events that promote nuclear exclusion and changes in gene expression. We will use cutting-edge mouse genetics and cre-dependent viral tools that allow for time-delimited and cell-type specific manipulation of nucleus accumbens core neurons during drug taking and relapse events. Aim 1. Molecular and Cellular Mechanisms: In this aim, we will determine how cocaine and heroin SA regulate HDAC5’s redox-sensitive posttranslational modifications, subcellular distribution, genomic binding and regulation of gene expression. Aim 2. Circuit Specificity: In this aim, we will take a cutting-edge molecular genetic approach to dissect the cell-type specific roles for HDAC5 to negatively-regulate cocaine and heroin drug seeking. Aim 3. Treatment: In this aim, we will analyze the regulation of HDAC5 by NAC, and test the role of HDAC5 in the long-lasting ability of NAC to reduce reinstatement of heroin and cocaine seeking.

项目摘要 – 项目 1 Cowan 治疗药物成瘾的一个主要挑战是对药物成瘾的分子机制了解甚少。吸毒会导致大脑功能发生持续变化，即使在长期吸毒后也有利于寻求毒品长期戒毒涉及表观遗传过程，涉及染色质重塑酶，组蛋白脱乙酰酶 5 (HDAC5)，位于纹状体中型多棘神经元中，其功能是限制多种与成瘾相关的行为，包括恢复可卡因和海洛因的寻求。 HDAC5 在吸毒期间和吸毒后的调节和功能很复杂，而且人们对可卡因和吸毒后知之甚少。海洛因产生活性氧和氮（ROS/RNS），改变细胞的氧化还原状态，并且氧化还原介导的半胱氨酸硫醇修饰改变靶蛋白的结构/功能，包括 IIa 类用抗氧化剂和谷胱甘肽前体 N- 重复治疗动物或人类。乙酰半胱氨酸（NAC），降低恢复可卡因和海洛因寻求的脆弱性，以及 NAC 阻止 ROS 促进的 HDAC5 核输出项目 1 的长期目标是了解氧化还原。 HDAC5 和 NAC 调节海洛因和可卡因复吸的蛋白质信号传导和表观遗传机制行为，希望找到更好的治疗药物成瘾的治疗策略。接下来是：（1）可卡因和海洛因产生的氧化应激修饰HDAC5中的半胱氨酸硫醇基团伏隔核，促进核输出并减少 HDAC5 的抗复发作用，以及 (2) 重复 NAC 治疗的抗复发作用至少部分归因于其保护 HDAC5 的能力我们将使用促进核排斥和基因表达变化的 ROS 信号事件。尖端的小鼠遗传学和 cre 依赖性病毒工具，可实现时间限定和细胞类型特异性在吸毒和复发事件期间控制伏隔核核心神经元。目标 1. 分子和细胞机制：在这个目标中，我们将确定可卡因和海洛因 SA 调节 HDAC5 的氧化还原敏感翻译后修饰、亚细胞分布、基因组结合和基因表达的调控。目标 2. 电路特异性：在这个目标中，我们将采用尖端的分子遗传学方法来剖析 HDAC5 负调节可卡因和海洛因药物寻找的细胞类型特异性作用。目标3.治疗：在此目标中，我们将分析NAC对HDAC5的调节，并测试HDAC5的作用 NAC 具有减少海洛因和可卡因寻求恢复的长期能力。