Elucidating the role of exosomal miR-21 in SIV/HIV neurological dysfunction

 描述：HIV相关神经认知障碍(HAND)的严重程度不等，从无症状到轻微的神经认知障碍，再到最严重的衰弱痴呆症，在感染HIV-1的一部分人中发展。Hand是间接神经毒性的结果，因为HIV感染大脑中的巨噬细胞和小胶质细胞，但不感染神经元。HIV-1感染脑内神经毒性的分子机制在很大程度上仍不清楚。我们和其他人的研究发现了一类调节RNAs，microRNAs(MiRNA)，它在HIV-1相关的神经疾病中调节失调。最近的发现表明，miRNAs可以在细胞外小泡中携带，如外切体，这些小泡最近成为大脑中细胞间通讯的重要媒介。Exosome可以将它们的货物释放到靶细胞中，并触发下游信号通路。我们特别感兴趣的是了解这种外切体携带的miRNAs对神经元的影响。特别是，我们将研究miR-21。我们之前已经发现，在SIV/HIV感染期间，miR-21在大脑中显著上调。我们现在发现它存在于感染的大脑中的巨噬细胞中，我们的体外研究表明，人和小鼠的巨噬细胞都在外体中释放miR-21。这些miRNAs具有G/U富集区，能够激活TLR7/TLR8。我们认为miR-21和类似的miRNAs是潜在的神经毒性因子，在HIV-1诱导的大脑损伤过程中特异性地释放。在这里，我们假设研究外体miR-21及其在SIV/HIV-1感染中对神经元的影响。这些研究将在两个特定的目标下进行：(1)在特定的目标1中，我们将利用稳健的策略从SIV和HIV-1感染的脑组织中分离外切体，对它们进行表征，并确定SIV/HIV诱导的外切体miR-21的变化。(2)特异性靶点2是针对外体miR-21感染SIV/HIV-1过程中诱导神经损伤的分子信号通路而设计的。我们将研究外体miR-21是否激活Toll样受体，以及哪些下游信号通路可以损害神经元健康。这些实验将扩大我们对HIV脑感染期间加剧神经元损伤的机制的了解，从而为进一步开展预防手部长期神经元损伤的治疗研究奠定坚实的基础。

 DESCRIPTION: HIV-associated neurocognitive disorders (HAND), varying in severity from an asymptomatic to mild neurocognitive impairment to in its most serious form a debilitating dementia, develop in a subset of individuals infected with HIV-1. HAND results from an indirect neurotoxicity, as HIV infects macrophages and microglia, but not neurons, in the brain. The molecular mechanisms underlying neurotoxicity by HIV-1 infection in the brain are still largely unknown. Our studies and those of others have discovered a class of regulatory RNAs, microRNAs (miRNA) that are dysregulated in HIV-1 associated neurological disease. Recent findings indicate that miRNAs can be carried in extracellular vesicles such as exosomes, which have lately emerged as important mediators of cell-to-cell communication in the brain. Exosomes can release their cargo into target cells and trigger downstream signaling pathways. We are particularly interested in understanding the effect of such exosome-carried miRNAs on neurons. In particular, we will study miR-21. We have previously identified that miR-21 is significantly upregulated during SIV/HIV infection in the brain. We now find it is present within macrophages in the infected brain, and our in vitro studies reveal both human and mouse macrophages release miR-21 in exosomes. These miRNAs had a G/U rich region, capable of activating TLR7/TLR8. We believe that miR-21 and similar miRNAs are potential neurotoxic factors and are specifically released during HIV-1 induced insult to the brain. Here we hypothesize to study exosomal miR-21 and its effect on neurons in SIV/HIV-1 infection. These studies will be done in two specific aims; (1) In specific aim 1 we will utilize a robust strategy o isolate exosomes form SIV and HIV-1 infected brain tissue, characterize them, and determine SIV/HIV induced alterations in exosomal miR-21. (2) Specific aim 2 is specifically designed identify induction of neuro-injurious molecular signaling pathways during SIV/HIV-1 infection by exosomal miR-21. We will examine whether exosomal miR-21 activates toll like receptors and which downstream signaling pathways can harm neuronal health. These experiments will expand our knowledge on understanding the mechanisms accounting for the exacerbated neuronal damage during HIV-infection of the brain and therefore build a strong ground to build further therapeutic studies for the prevention of long-term neuronal damage in HAND.