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 HIV-1相关性神经功能障碍(HAND)的临床病程，潜在的机制 可卡因调节中枢神经系统(CNS)的病理仍然难以捉摸。神经性炎症涉及 强健的小胶质细胞激活已成为HIV感染和药物相关的重要表型 尽管出现了联合抗逆转录病毒疗法(CART)，但仍存在滥用。与艾滋病毒相关的潜在原因 神经炎可能归因于这样一个事实，即病毒感染和前病毒的形成 DNA、CART不能有效抑制Tat和gp120等有毒病毒基因产物的表达。 继续存在于中枢神经系统等组织中。此外，与CART上的HIV阳性受试者类似，SIV- CART上受感染的恒河猴也表现出神经胶质细胞的激活增加，这被证明是 与各种标志性microRNAs(MiRs)的调节失调有关。新出现的证据也表明 可卡因等药物在调节神经胶质细胞活化和MIR全球变化中的作用。事实上，在最近的一次 我们发现，可卡因介导的小胶质细胞激活涉及miR-124的下调 在体外和体内均有表达。此外，我们还阐明了hiv tat介导的小胶质细胞。 迁移涉及miR-9的上调表达，并伴随着其靶细胞单核细胞的下调 趋化蛋白诱导蛋白1(MCPIP1)。因此我们假设可卡因和HIV都能调节TAT 分别通过两种不同的机制增加小胶质细胞的激活和迁移：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TLR4信号的增加 最终导致小胶质细胞活化增加，以及，b)小胶质细胞暴露于HIV TAT上调 MiR-9的表达反过来通过下调靶MCPIP1而促进小胶质细胞的迁移。 三位有经验的PI(Buch、Hu和Guo博士)将共同领导这个项目，以实现拟议的目标。这 建议响应RFA(RFA-DA-16-012)，重点关注表观基因组和非编码RNA调控 在艾滋病毒/艾滋病和药物滥用方面。

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.