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: 10409766
• 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/10409766
• 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 药物成瘾是一种慢性复发性疾病，其特征是强迫性药物寻求， 使用，尽管有害的后果。更具体地说，阿片类药物使用障碍（OUD），往往源于 滥用处方阿片类止痛药是一个紧迫的社会和健康危机， 每年约有50，000例过量死亡，每年造成785亿美元的医疗负担 治疗，生产力损失和法律的费用（见NIDA网站）。虽然有效的治疗方法 存在阿片类药物过量事件，缺乏长期禁欲的有效治疗方法， 预防复发强调迫切需要替代方法来研究OUD。 除了对神经元功能的直接作用外，已知阿片类药物还直接作用于 小胶质细胞小神经胶质细胞是大脑中的常驻免疫细胞， 神经炎症是一种旨在恢复稳态的生理过程，通常响应于神经炎症， 对中枢神经系统的创伤性、化学性或缺血性损伤。神经炎症的标志 是小胶质细胞激活，而小胶质细胞激活的转录机制 在组蛋白的表观遗传重塑的控制下。在OUD的背景下，以前 表明阿片类药物可以诱导小胶质细胞的激活，并且减少神经炎症可以抑制 对阿片类止痛药的渴望 考虑到表观遗传学在成瘾中的已知作用和小胶质细胞在这一过程中的新作用， 疾病，我们建议调查小胶质细胞激活的表观遗传基础OUD。更 具体来说，我们将集中在组蛋白赖氨酸甲基化的变化，在小胶质细胞的大脑奖励 系统以及这些变化如何与阿片类药物不同阶段的转录程序相一致- 通过使用静脉注射的小鼠模型， 瑞芬太尼自我给药（IVSA）。此外，我们将探讨这种表观遗传的作用， 调节阿片样物质诱导的小胶质细胞活化，阿片样物质寻求和复发的修饰 药理学和遗传操作Kdm 6 b，组蛋白赖氨酸脱甲基酶富集， 小胶质细胞总之，这些实验的结果不仅有可能扩大我们的研究范围， 理解OUD背后的表观遗传机制，而是推动成瘾领域 表观遗传学超越了神经元，进入细胞类型，可以产生令人兴奋的新的治疗途径， 治疗这种毁灭性的疾病。