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

阐明外泌体 miR-21 在 SIV/HIV 神经功能障碍中的作用

• 批准号: 8995690
• 负责人: HOWARD S FOX
• 金额: $ 18.81万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995690
• 关键词: Accounting; Address; Affect; Anti-Retroviral Agents; Autopsy; Brain; Cell Communication; Cells; Cellular biology; Clinical; Cognition Disorders; Communication; Data; Dementia; Environment; Event; Experimental Models; Foundations; Genetic; Goals; Grant; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Health; Human; Impaired cognition; In Vitro; Individual; Infection; Knock-out; Knowledge; Lead; Light; Macaca; Macaca mulatta; Measures; Mediator of activation protein; Methods; MicroRNAs; Microglia; Modeling; Molecular; Mus; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neurologic Dysfunctions; Neurons; Pathway interactions; Pharmaceutical Preparations; Prevention; Proteins; Receptor Signaling; Recording of previous events; Records; Research; Research Design; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; SIV; SIV encephalitis; Sampling; Series; Severities; Signal Pathway; Signal Transduction; Specimen; TLR7 gene; TLR8 gene; Therapeutic; Therapeutic Studies; Toll-like receptors; Wild Type Mouse; brain tissue; design; exosome; expectation; extracellular vesicles; inhibitor/antagonist; innovation; interest; macrophage; mild neurocognitive impairment; mouse model; nervous system disorder; neuropathology; neurotoxic; neurotoxicity; nonhuman primate; novel; pandemic disease; protein biomarkers; public health relevance; research study; therapeutic target

 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.

 产品说明：HIV相关的神经认知障碍（HAND），其严重程度从无症状到轻度神经认知损害到最严重形式的衰弱性痴呆，在感染HIV-1的个体的子集中发展。HAND由间接神经毒性引起，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。脑中HIV-1感染引起的神经毒性的分子机制在很大程度上仍然未知。我们的研究和其他人的研究发现了一类调节RNA，即在HIV-1相关神经系统疾病中失调的microRNA（miRNA）。最近的研究结果表明，miRNA可以携带在细胞外囊泡，如外来体，这是最近出现的重要介质的细胞间通讯在大脑中。外泌体可以将其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泌体携带的miRNA对神经元的影响。特别是，我们将研究miR-21。我们先前已经确定，miR-21在SIV/HIV感染期间在大脑中显著上调。我们现在发现它存在于受感染大脑中的巨噬细胞内，我们的体外研究表明人类和小鼠巨噬细胞都在外泌体中释放miR-21。这些miRNAs具有富含G/U的区域，能够激活TLR 7/TLR 8。我们认为miR-21和类似的miRNA是潜在的神经毒性因子，并且在HIV-1诱导的脑损伤期间特异性释放。在这里，我们假设研究外泌体miR-21及其对SIV/HIV-1感染中神经元的影响。这些研究将在两个具体目标中进行;（1）在具体目标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泌体，表征它们，并确定SIV/HIV诱导的外泌体miR-21的改变。(2)具体目标2是专门设计的，用于鉴定外泌体miR-21在SIV/HIV-1感染期间对神经损伤性分子信号传导途径的诱导。我们将研究外泌体miR-21是否激活Toll样受体，以及哪些下游信号通路会损害神经元的健康。这些实验将扩大我们的知识，了解艾滋病毒感染的大脑过程中加剧的神经元损伤的机制，因此建立一个坚实的基础，建立进一步的治疗研究，预防长期的神经元损伤的手。