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.

项目总结 毒瘾是一种慢性、复发性疾病，其特征是强迫性寻求毒品和 使用，不顾有害的后果。更具体地说，阿片使用障碍(OUD)，通常源于 滥用处方阿片类止痛药，代表着紧迫的社会和健康危机，负责任 每年约有50,000人死于服药过量，每年的医疗负担为785亿美元 在美国，治疗、生产力损失和法律费用(见NIDA网站)。虽然有效的治疗方法 存在阿片类药物过量事件，缺乏有效的长期戒断疗法和 预防故态复萌突出表明迫切需要有替代的方法来研究OUD。 除了对神经元功能的直接影响外，阿片类药物也已知直接作用于 小胶质细胞。小胶质细胞是大脑中的常驻免疫细胞，是 神经炎症，一种旨在恢复内稳态的生理过程，通常是对 对中枢神经系统的创伤性、化学性或缺血性侮辱。神经炎的标志 是小胶质细胞的激活，而小胶质细胞激活背后的转录机制起作用 在组蛋白表观遗传重塑的控制下。在OUD的背景下，它以前是 研究表明，阿片类药物可以诱导小胶质细胞激活，神经炎症的减少可以抑制 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以及小胶质细胞在成瘾中的新角色 疾病，我们建议调查小胶质细胞激活的表观遗传学基础。更多 具体地说，我们将重点研究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不同阶段的转录程序相协调- 使用小鼠静脉注射模型服用(维持、早期戒断和渴求) 瑞芬太尼自主给药(IVSA)。此外，我们将探索这种表观遗传学的作用 阿片类药物诱导的小胶质细胞活化、阿片寻求和复发的调控 富集组蛋白赖氨酸去甲基酶KDM6B的药理和遗传操作 小胶质细胞。总而言之，这些实验的结果不仅有可能扩大我们的 了解OUD背后的表观遗传机制，但更多的是推动成瘾领域 表观遗传学超越神经元，进入细胞类型，可能产生令人兴奋的新的治疗途径 治疗这种毁灭性疾病的方法。