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HIV-1 gp120-induced Endothelial Cell Dysfunction

HIV-1 gp120 诱导的内皮细胞功能障碍

基本信息

批准号：
7213429
负责人：
GEORGETTE D. KANMOGNE
金额：
$ 10.64万
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：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213429
关键词：
AIDS Dementia Complex Affect Antibodies Apoptosis Apoptotic BCL2 gene Blood - brain barrier anatomy Brain Brain Injuries CCR5 gene CD95 Antigens CXCR4 gene Calcium Caspase Cessation of life Chemokine (C-C Motif) Receptor 5 Complex Cyclic AMP-Dependent Protein Kinases Data Dementia Dextrans Disruption Endothelial Cells Endothelium Exclusion Fluorescein Fluoresceins Fluorescent Antibody Technique Functional disorder Genes HIV HIV Envelope Protein gp120 HIV encephalitis HIV-1 Human Immunofluorescence Immunologic Infection Invaded Knowledge Label Laboratories Ligands Measures Mediating Morbidity - disease rate Neuraxis Neuropathogenesis Pathogenesis Pathway interactions Patients Permeability Play Protein Kinase C Protein Tyrosine Kinase Proteins Role Signal Transduction Pathway Staging System Testing Therapeutic Therapeutic Intervention Tight Junctions Trypan Blue Tumor Necrosis Factor Ligand Superfamily Member 6 Viral Virus Diseases Western Blotting base cell injury cerebral atrophy chemokine receptor design dextran env Gene Products gp-120 Antigen improved neurotoxic novel occludin prevent research study

项目摘要

DESCRIPTION (provided by applicant): The human immunodeficiency virus (HIV) invades the brain in the early stages of infection For patients in the advanced stage of infection, dysfunction of the central nervous system (CNS) is a common cause of morbidity and often leads to progressive dementia, cerebral atrophy and death. Evidence suggest that HIV and /or HIV-associated proteins are critical to the pathogenesis of the HIV-associated dementia (HAD)complex .To elucidate the pathogenesis of HAD, it is important to understand by what mechanisms HIV invades the brain. Breakdown of the blood-brain barrier is commonly seen in patients with HAD, despite the lack of productive HIV-infection of the brain endothelium. The HIV-1 envelope protein gp120 is present in the brain of patients with HIV encephalitis, and is neurotoxic Recent evidence from our laboratory, and by others, suggests a direct effect of gp120 on the brain endothelium. It is our hypothesis that gp120 directly causes blood-brain barrier dysfunction and plays a major role in viral invasion of the brain To test this hypothesis, we plan the following aims. Aim 1: To test the hypothesis that HIV-1 gp120 proteins are toxic to human brain microvascular endothelial cells and directly induce a disruption and/or damage of the blood-brain barrier we will measure endothelial cell permeability and apoptosis. Aim 2 To test the hypothesis that exposure of gp120 proteins to human brain microvascular endothelial cells result in the loss of tight junction proteins we will assess the expression of occludin, claudia-5 and zonula occludens-1 using western blotting and immunofluorescence. Aim 3: To determine if chemokine receptors are involved in gp120-induced blood-brain barrier disruption and/or damage Aim 4: To determine the signal transduction pathways involved in gp120-induced blood-brain barrier dysfunction. Data from these experiments will help determine the role that gp120 plays in the breach of blood-brain barrier integrity and HIV invasion of the brain, and will suggest therapeutic approaches to preventing gp120-mediated dysfunction of the brain endothelium during HIV infection.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）在感染的早期阶段侵入大脑对于感染晚期的患者，中枢神经系统（CNS）功能障碍是发病的常见原因，通常导致进行性痴呆、脑萎缩和死亡。有证据表明HIV和/或HIV相关蛋白在HIV相关痴呆（HAD）综合征的发病机制中起着关键作用，为了阐明HAD的发病机制，了解HIV通过何种机制侵入大脑是非常重要的。尽管脑内皮缺乏有效的艾滋病毒感染，但血脑屏障的破坏在HAD患者中很常见。HIV-1包膜蛋白gp 120存在于HIV脑炎患者的大脑中，并且具有神经毒性。我们实验室和其他实验室的最新证据表明，gp 120对脑内皮细胞有直接影响。我们的假设是，gp 120直接导致血脑屏障功能障碍，并在病毒入侵大脑中起主要作用。为了验证这一假设，我们计划以下目标。目标1：为了检验HIV-1 gp 120蛋白对人脑微血管内皮细胞有毒并直接诱导血脑屏障破坏和/或损伤的假设，我们将测量内皮细胞通透性和凋亡。目的2为了验证gp 120蛋白暴露于人脑微血管内皮细胞导致紧密连接蛋白丢失的假设，我们将使用western印迹和免疫荧光法评估闭合蛋白、claudia-5和闭合小带-1的表达。目标三：确定趋化因子受体是否参与gp 120诱导的血脑屏障破坏和/或损伤目的4：确定参与gp 120诱导的血脑屏障功能障碍的信号转导途径。这些实验的数据将有助于确定gp 120在破坏血脑屏障完整性和HIV入侵大脑中所起的作用，并将提出预防HIV感染期间gp 120介导的脑内皮功能障碍的治疗方法。