HIV Tat & cocaine-mediated alterations in microglial migration & activation involve epigenetic reulation of miRNAs

摘要： 药物滥用和HIV-1是两个相互关联的全球健康危机。尽管可卡因滥用对儿童的影响是公认的， HIV-1相关神经系统疾病（HAND）的临床过程， 可卡因调节中枢神经系统（CNS）病理学仍然难以捉摸。神经炎症累及 强烈的小胶质细胞活化已经成为HIV感染和药物治疗的重要表型和相关性 尽管出现了联合抗逆转录病毒疗法（cART），但仍存在滥用现象。艾滋病毒相关的根本原因 神经炎症可能归因于病毒感染和前病毒形成后， DNA，cART在消除毒性病毒基因产物如达特和gp 120的表达方面是无效的， 继续存在于诸如CNS的组织中。此外，与接受cART的HIV阳性受试者相似，SIV- 接受cART治疗的感染恒河猴也表现出增加的胶质细胞活化， 与各种标志性microRNA（miR）的失调相关。新出现的证据也指出， 药物如可卡因在介导神经胶质细胞活化与miR的整体变化中的作用。事实上，在最近的一次 这一发现表明，可卡因介导的小胶质细胞活化涉及miR-124的下调 在体外和体内表达。此外，我们还阐明了HIV达特介导的小胶质细胞 迁移涉及miR-9的上调表达及其靶细胞单核细胞的下调 趋化蛋白诱导蛋白1（MCPIP 1）。因此，我们假设可卡因和HIV达特都能调节 通过两种不同的机制分别增加小胶质细胞活化和迁移：a）可卡因介导 miR-124通过其启动子的DNA甲基化下调，进而导致TLR 4信号传导增加 最终导致小胶质细胞活化增加，和，B）小胶质细胞暴露于HIV达特上调 miR-9的表达反过来导致通过下调靶MCPIP 1增强小胶质细胞迁移。 三位经验丰富的PI（Drs. Buch，Hu和Guo）将共同领导该项目，以实现拟议的目标。这 该提案响应RFA（RFA-DA-16-012），重点关注表观基因组和非编码RNA调控 艾滋病毒/艾滋病和药物滥用。

Abstract: Drug abuse and HIV-1 are two linked global health crises. Despite the recognized impact of cocaine abuse on the clinical course of HIV-1-associated neurological disorder (HAND), the mechanisms underlying the ability of cocaine to modulate central nervous system (CNS) pathology remain elusive. Neuroinflammation involving robust microglial activation has emerged as an important phenotype and correlate of HIV infection and drug abuse despite the advent of combined anti-retroviral therapy (cART). The underlying cause of HIV-associated neuroinflammation is likely attributable to the fact that following virus infection and formation of the proviral DNA, cART is ineffective in abrogating the expression of toxic viral gene products such as Tat and gp120, that continue to be present in tissues such as the CNS. Furthermore, similar to HIV positive subjects on cART, SIV- infected rhesus macaques on cART also demonstrate increased glial activation, which was shown to be associated with dysregulation of various signature microRNAs (miRs). Emerging evidence also points to the role of drugs such as cocaine in mediating glial activation with global changes in miRs. In fact, in a recent finding, we demonstrate that cocaine-mediated activation of microglia involves down-regulation of miR-124 expression both in vitro and in vivo. Furthermore, we have also elucidated that HIV Tat mediated microglial migration involves upregulated expression of miR-9 with a concomitant downregulation of its target, monocyte chemotactic protein-induced protein 1 (MCPIP1). We thus hypothesize that both cocaine and HIV Tat modulate increased microglial activation and migration respectively, via two distinct mechanisms: a) cocaine mediates downregulation of miR-124 via DNA methylation of its promoter, leading in turn, to increased TLR4 signaling that culminates into increased microglial activation and, b) exposure of microglia to HIV Tat upregulates the expression of miR-9 leading in turn, to enhanced microglial migration via downregulation of the target MCPIP1. Three experienced PIs (Drs. Buch, Hu, & Guo) will co-lead this project to accomplish the proposed goals. This proposal is responsive to the RFA (RFA-DA-16-012) focusing on epigenomic and non-coding RNA regulation in HIV/AIDS and substance abuse.