Microglia and Epigenetic Regulation in Opioid Addiction

阿片类药物成瘾中的小胶质细胞和表观遗传调控

• 批准号: 10201552
• 负责人: Luis Miguel Tuesta
• 金额: $ 46.05万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10201552
• 关键词: Abstinence; Affect; Attention; Brain; Cells; Chemicals; Chronic; Disease; Drug Addiction; Epigenetic Process; Event; Genetic Transcription; Goals; Health; Histones; Homeostasis; Immune; Intravenous; Legal; Lysine; Maintenance; Medical; Methylation; Microglia; Modification; National Institute of Drug Abuse; Neuraxis; Neurons; Opiate Addiction; Opioid; Opioid Analgesics; Pharmaceutical Preparations; Pharmacology; Phase; Physiological Processes; Productivity; Proteins; Public Health; Recurrent disease; Relapse; Research; Rewards; Role; Self Administration; System; Therapeutic; Withdrawal; addiction; brain cell; cell type; cost; craving; disorder later incidence prevention; effective therapy; epigenetic regulation; experimental study; genetic manipulation; mouse model; neuroinflammation; novel therapeutics; opioid overdose; opioid use disorder; overdose death; prescription opioid misuse; programs; remifentanil; response; social; stem; therapeutically effective; web site

PROJECT SUMMARY Drug addiction is a chronic, relapsing disease characterized by compulsive drug seeking and use, despite harmful consequences. More specifically, opioid use disorder (OUD), often stemming from the misuse of prescription opioid painkillers, represents an urgent social and health crisis, responsible for approximately 50,000 yearly overdose deaths and incurring an annual burden of $78.5B in medical treatment, lost productivity and legal costs in the US (See NIDA website). While effective treatments exist for opioid overdose events, the lack of effective therapeutics for long-term abstinence and prevention of relapse highlight the pressing need for alternative approaches to study OUD. Moving beyond their direct effect on neuronal function, opioids are also known to act directly on microglia. Microglia are resident immune cells in the brain that serve as key drivers of neuroinflammation, a physiological process aimed at restoring homeostasis typically in response to a traumatic, chemical or ischemic insult to the central nervous system. A hallmark of neuroinflammation is microglial activation, and the transcriptional mechanisms underlying microglial activation operate under control of epigenetic remodeling of histone proteins. In the context of OUD, it has been previously shown that opioids can induce activation of microglia and that reduction in neuroinflammation can curb craving for opioid painkillers. Considering the known role of epigenetics in addiction and the emerging role of microglia in this disease, we propose to investigate the epigenetic underpinnings of microglial activation in OUD. More specifically, we will focus on the changes in histone lysine methylation in microglia of the brain reward system and how these changes comport with transcriptional programs across various phases of opioid- taking (maintenance, early withdrawal, and craving) by using a mouse model of intravenous remifentanil self-administration (IVSA). Furthermore, we will explore the role of this epigenetic modification in regulating opioid-induced microglial activation, opioid-seeking and relapse by pharmacological and genetic manipulation of Kdm6b, a histone lysine demethylase enriched in microglia. In conclusion, results from these experiments have the potential to not just broaden our understanding of the epigenetic mechanisms underlying OUD, but rather push the field of addiction epigenetics beyond the neuron and into cell types that could yield exciting new therapeutic avenues for the treatment this devastating disease.

项目摘要 吸毒成瘾是一种慢性，复发的疾病，其特征是寻求强迫性药物和 使用，尽管后果有害。更具体地说，阿片类药物使用障碍（OUD），通常是由 处方阿片类止痛药的滥用代表了紧急的社会和健康危机，负责 大约50,000年过量的死亡人数，每年负担为78.5B美元的医疗负担 美国的治疗，生产率损失和法律成本（请参阅NIDA网站）。同时有效治疗 存在阿片类药物过量事件，缺乏长期戒酒和 预防复发突出了对研究OUD的替代方法的紧迫需求。 超越其对神经元功能的直接影响，也已知阿片类药物直接作用于 小胶质细胞。小胶质细胞是大脑中的常驻免疫细胞，作为关键驱动因素 神经炎症，这是一种旨在恢复体内平衡的生理过程 对中枢神经系统的创伤，化学或缺血性侮辱。神经炎症的标志 是小胶质细胞激活，小胶质细胞激活的转录机制起作用 在控制组蛋白的表观遗传重塑下。在Oud的背景下，它以前是 表明阿片类药物可以诱导小胶质细胞激活，而神经炎症的减少可以抑制 渴望阿片类止痛药。 考虑表观遗传学在成瘾中的已知作用以及小胶质细胞在此中的新兴作用 疾病，我们建议研究OUD中小胶质细胞激活的表观遗传基础。更多的 具体而言，我们将重点介绍大脑奖励小胶质细胞中组蛋白赖氨酸甲基化的变化 系统以及这些变化如何与阿片类药物的各个阶段的转录程序相处 通过使用静脉内的鼠标模型进行（维护，提早提取和渴望） Remifentanil自我管理（IVSA）。此外，我们将探讨这种表观遗传学的作用 调节阿片类药物诱导的小胶质细胞激活，寻求阿片类药物和复发的修改 KDM6B的药理和遗传操纵，一种富含组蛋白的赖氨酸脱甲基酶 小胶质细胞。总之，这些实验的结果不仅有可能扩大我们的 了解Oud的表观遗传机制，而是推动成瘾的领域 神经元之外的表观遗传学并进入细胞类型，这些细胞类型可能会产生令人兴奋的新治疗途径 治疗这种毁灭性疾病。