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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：
7806523
负责人：
GEORGETTE D. KANMOGNE
金额：
$ 29.4万
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 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7806523
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 Figs - dietary 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 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

DESCRIPTION (provided by applicant): 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.

描述(由申请人提供)：血脑屏障(BBB)损害在HIV-1感染者中很常见，并与HIV-1相关性痴呆的发病机制有关。这一屏障的后部使子代病毒和激活的、感染HIV-1的巨噬细胞渗透到大脑，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分泌神经毒素，影响神经元功能，导致认知障碍。因此，阻止血脑屏障损伤是预防HIV-1感染后神经损伤的主要手段。要做到这一点，需要阐明HIV感染导致血脑屏障功能障碍的机制。我们利用一个明确的平台，整合了基因组学、蛋白质组学和细胞生物学系统，最近证明了HIV-1感染的巨噬细胞与人脑微血管内皮细胞接触，并刺激促炎细胞因子和趋化因子的自分泌和旁分泌级联反应，最终影响血脑屏障的结构和完整性。我们的初步工作，在体外和使用HIV感染者的脑微血管，证明了HIV-1诱导的炎症和对人脑内皮细胞的损伤涉及丝氨酸727处的STAT1激活。我们进一步证明，一种特异性的STAT1抑制剂氟达拉滨可以减少炎症和病毒感染性，减少病毒血症，胶质细胞和巨噬细胞在HIV脑炎小鼠脑内的渗透。基于这些观察，我们的假设是，STAT1在HIV-1诱导的BBB功能障碍中发挥关键作用，并调节巨噬细胞-内皮细胞的相互作用。我们假设，通过影响STAT1通路，BBB功能障碍可以逆转，从而保护屏障的完整性。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在这些变化中的作用。这是基于我们的初步观察，HIV-1感染的巨噬细胞炎症反应改变了内皮细胞骨架。在目标2中，我们将研究在HIV感染的背景下，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HIV-1脑炎的动物模型来验证我们的假设，即STAT1在体内介导艾滋病毒诱导的血脑屏障损伤。这些研究将深入了解细胞因子和艾滋病毒在血脑屏障传递信号的机制，艾滋病毒感染中发生的失调并导致血脑屏障功能障碍。相关性：目前世界上有4000万人感染艾滋病毒/艾滋病；在这些感染者中，神经系统并发症很常见。HIV侵入大脑破坏脑内皮细胞，然后感染脑巨噬细胞并损伤神经元，导致认知障碍，有时还会导致痴呆症。这项提案中的工作将帮助我们了解艾滋病毒如何破坏大脑内皮并进入大脑，如何防止病毒进入大脑，以及艾滋病毒相关痴呆。