Blood brain barrier immune compromise in NeuroAIDS

NeuroAIDS 中的血脑屏障免疫受损

基本信息

批准号：
8247819
负责人：
GEORGETTE D. KANMOGNE
金额：
$ 29.11万
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：
2008
资助国家：
美国
起止时间：
2008-05-02 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8247819
关键词：
AIDS Dementia Complex AIDS neuropathy AIDS/HIV problem Actins Address Adhesives Affect Animal Model Animals Antibodies Award Biochemical Biology Blood - brain barrier anatomy Brain Brain Injuries CCL2 gene CXCL10 gene Cell Communication Cell Nucleus Cell physiology Cells Cellular Morphology Cellular Structures Central Nervous System Diseases Coculture Techniques Cognitive deficits Complex Cytokine Inducible SH2-Containing Protein Cytoskeleton DNA Binding DNA Sequence Rearrangement Dementia Electrical Resistance Encephalitis Endothelial Cells Endothelium Event Extravasation Family member Focal Adhesions Functional disorder Genetic Transcription Genomics Gliosis HIV HIV Envelope Protein gp120 HIV Infections HIV encephalitis HIV-1 Human IL8 gene Immune Immunohistochemistry Impaired cognition Impairment In Vitro Individual Infection Infiltration Inflammation Inflammatory Inflammatory Response Injury Interleukin-6 Janus kinase Laboratories Lead Leukocytes Life Ligands Link Mediating Membrane Messenger RNA Microfilaments Microglia Modeling Molecular Mus NOD/SCID mouse Nervous System Trauma Nervous system structure Neuroglia Neurologic Neuronal Injury Neurons Neuropathogenesis Neurotoxins Pathogenesis Pathway interactions Patients Permeability Play Proteins Proteomics Research Research Support Role STAT1 gene Serine Signal Transduction Stress Fibers Structure System Testing Therapeutic Tight Junctions Time Tyrosine Viral Viral Proteins Viremia Virus Work abstracting adherent junction autocrine base biological systems chemokine cytokine exposed human population fludarabine in vivo inhibitor/antagonist injured insight macrophage migration monocyte novel paracrine prevent protein inhibitor of activated STAT 1 receptor binding research study response transcription factor

项目摘要

Abstract: Blood-brain barrier (BBB) compromise is common in HIV-1-infected individuals and is implicated in the pathogenesis of HIV-1-associated dementia. Breech of this barrier allows progeny virus and activated, HIV-1- infected macrophages to infiltrate the brain, disseminate virus to perivascular macrophages and microglia. Infected cells in the brain secrete neurotoxins that affect neuronal function and lead to cognitive impairments. Therefore, a principal means to prevent neurological injury following HIV-1 infection is to halt BBB injury. To accomplish this, the mechanisms through which HIV infection leads to BBB dysfunction need be elucidated. Using a defined platform, integrating genomics, proteomics and cell biological systems, we recently demonstrated that HIV-1-infected macrophages engage human brain microvascular endothelial cells and incite an autocrine and paracrine cascade of pro-inflammatory cytokines and chemokines that ultimately affect the structure and integrity of the BBB. Our preliminary work, in vitro and using brain microvessels from HIV- infected humans, demonstrated that HIV-1-induced inflammation and injury to human brain endothelial cells involve activation of STAT1 at serine 727. We further demonstrated that Fludarabine, a specific STAT1 inhibitor, reduced inflammation and viral infectivity, reduced viremia, gliosis and macrophage infiltration in the brain of HIV encephalitic mice. Based on these observations, it is our hypothesis that STAT1 play a critical role in HIV-1-induced BBB dysfunction and modulates macrophage-endothelial interactions. We hypothesize that by affecting STAT1 pathways, BBB dysfunction can be reversed leading to protection of the barrier's integrity. This hypothesis will be addressed in the following specific aims: in Aim 1, we will investigate the effects of HIV-1 and viral-induced cytokines on the endothelial cytoskeleton, and decipher the role of STAT-1 on these alterations. This is based on our preliminary observation that HIV-1-infected macrophage inflammatory responses alter the endothelial cytoskeleton. In Aim 2, we will investigate the role of STAT1 in endothelial cell function and endothelial-macrophage interaction in the context of HIV infection. Finally in Aim 3, we will test our hypothesis that STAT1 mediates HIV-induced BBB injury in vivo, using an animal model of HIV-1 encephalitis. These studies will provide insight into the mechanisms by which cytokines and HIV transduce signals at the BBB, dysregulations that occurs in HIV infection and lead to BBB dysfunction. Relevance: Forty-million people in the world are currently living with HIV/AIDS; and neurological complications are common among these infected individuals. HIV infiltrates the brain damaging the brain endothelium, then infects brain macrophages and injures neurons, resulting in cognitive deficits and sometimes dementia. The work in this proposal will help us understand how HIV damages the brain endothelium and enters the brain, how to prevent viral entry into the brain, and HIV-associated dementia.

抽象的：血脑屏障 (BBB) 受损在 HIV-1 感染者中很常见，并且与 HIV-1相关痴呆的发病机制。突破这个屏障允许后代病毒和激活的 HIV-1- 感染的巨噬细胞渗入大脑，将病毒传播到血管周围的巨噬细胞和小胶质细胞。大脑中受感染的细胞会分泌神经毒素，影响神经元功能并导致认知障碍。因此，预防HIV-1感染后神经损伤的主要方法是阻止BBB损伤。到为了实现这一目标，需要阐明 HIV 感染导致 BBB 功能障碍的机制。使用定义的平台，整合基因组学、蛋白质组学和细胞生物系统，我们最近证明 HIV-1 感染的巨噬细胞参与人脑微血管内皮细胞并煽动促炎细胞因子和趋化因子的自分泌和旁分泌级联反应最终影响 BBB 的结构和完整性。我们的初步工作是在体外并使用来自艾滋病毒的脑微血管- 感染人类，证明 HIV-1 诱导炎症和人脑内皮细胞损伤涉及丝氨酸 727 处 STAT1 的激活。我们进一步证明了 Fludarabine（一种特定的 STAT1）抑制剂，减少炎症和病毒感染性，减少病毒血症、神经胶质增生和巨噬细胞浸润 HIV脑炎小鼠的大脑。基于这些观察，我们假设 STAT1 发挥着关键作用在 HIV-1 诱导的 BBB 功能障碍中发挥作用并调节巨噬细胞-内皮相互作用。我们假设通过影响 STAT1 通路，可以逆转 BBB 功能障碍，从而产生保护作用屏障的完整性。这一假设将在以下具体目标中得到解决：在目标 1 中，我们将研究 HIV-1 和病毒诱导的细胞因子对内皮细胞骨架的影响，并破译 STAT-1 在这些改变中的作用。这是基于我们的初步观察，即 HIV-1 感染者巨噬细胞炎症反应改变内皮细胞骨架。在目标 2 中，我们将研究 HIV 感染背景下 STAT1 在内皮细胞功能和内皮-巨噬细胞相互作用中的作用。最后，在目标 3 中，我们将使用以下方法检验我们的假设：STAT1 在体内介导 HIV 诱导的 BBB 损伤 HIV-1脑炎动物模型。这些研究将深入了解细胞因子的作用机制 HIV 会在 BBB 上转导信号，HIV 感染时会出现失调并导致 BBB 功能障碍。关联：目前世界上有四千万人感染艾滋病毒/艾滋病；和神经系统并发症是在这些感染者中很常见。 HIV 侵入大脑，损害脑内皮，然后感染大脑巨噬细胞并损伤神经元，导致认知缺陷，有时甚至导致痴呆。这该提案中的工作将帮助我们了解艾滋病毒如何损害大脑内皮并进入大脑，如何防止病毒进入大脑以及与艾滋病毒相关的痴呆症。