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

基本信息

批准号：
8848625
负责人：
HOWARD S FOX
金额：
$ 22.58万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-15 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848625
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 Vesicle Wild Type Mouse brain tissue design expectation extracellular inhibitor/antagonist innovation interest macrophage mild neurocognitive impairment mouse model nervous system disorder neuropathology neurotoxic neurotoxicity nonhuman primate novel pandemic disease public health relevance research study therapeutic target

项目摘要

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.

描述：与艾滋病毒相关的神经认知障碍（手），严重程度从渐近神经认知障碍到最严重的衰减痴呆症，在感染HIV-1的个体中发展。手动是由间接神经毒性引起的，因为艾滋病毒感染巨噬细胞和小胶质细胞，但不是大脑中的神经元。大脑中HIV-1感染神经毒性的分子机制仍然很大程度上是未知的。我们的研究和其他研究发现了一类调节性RNA，microRNA（miRNA）在HIV-1相关的神经系统疾病中失调。最近的发现表明，miRNA可以在细胞外蔬菜（例如外泌体）中携带，这些蔬菜最近出现了大脑中细胞对细胞通信的重要介质。外泌体可以将其货物释放到目标细胞中，并触发下游信号通路。我们特别有兴趣了解这种外泌体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，在大脑中SIV/HIV感染期间，miR-21已显着更新。我们现在发现它存在于感染大脑中的巨噬细胞中，我们的体外研究揭示了人类和小鼠巨噬细胞在外泌体中释放miR-21。这些miRNA具有富含G/U的区域，能够激活TLR7/TLR8。我们认为，miR-21和类似的miRNA是潜在的神经毒性因素，在HIV-1引起的侮辱期间特别释放。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。这些研究将以两个具体的目的进行。（1）在特定目标1中，我们将使用强大的策略O分离外泌体形成SIV和HIV-1感染的脑组织，并确定SIV/HIV诱导的外泌体miR-21的改变。（2）特定的目标2是专门设计的，可以识别外泌体miR-21在SIV/HIV-1感染过程中神经伤害分子信号通路的诱导。我们将检查外泌体miR-21是否激活像受体一样激活Toll，以及哪些下游信号通路会损害神经元健康。这些实验将扩大我们对理解大脑HIV感染加重神经元损害的机制的知识，因此建立了强大的基础，以建立进一步的治疗研究，以预防手头上的长期神经元损害。