PPAR-gamma-mediated neuroprotection against HIV-1 and alcohol CNS injury

PPAR-γ介导的针对HIV-1和酒精中枢神经系统损伤的神经保护作用

基本信息

批准号：
7786873
负责人：
Yuri Persidsky
金额：
$ 1.62万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7786873
关键词：
3-nitrotyrosine AIDS Dementia Complex Acetaldehyde Address Affect Agonist Alcohol abuse Alcohols Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Attenuated Biological Assay Blood - brain barrier anatomy Brain Cell model Cells Chronic Clinical Cognitive deficits Data Development Down-Regulation Encephalitis Endothelial Cells Endothelium Enzymes Ethanol Functional disorder GTP Binding Generations Glutamates HIV HIV-1 Human Immune Immune response Immunity Impairment In Vitro Individual Infection Infiltration Inflammation Inflammatory Injury Interferons Interleukin-6 Interleukins Lead Lymphocyte Measures Mediating Microglia Modeling Monomeric GTP-Binding Proteins Mononuclear Nerve Degeneration Neuraxis Neuronal Injury Neurons Neurotoxins Non obese Oxidative Stress PPAR gamma Peripheral Blood Lymphocyte Permeability Phenotype Production Proteins Reactive Oxygen Species Regulatory Pathway Rho-associated kinase Role SCID Mice Structural Protein Superoxide Dismutase Symptoms Synapses Testing Therapeutic Tight Junctions Toxic effect Translations Tumor Necrosis Factor-alpha Tumor Necrosis Factors Up-Regulation Viral Viremia Virus Work alcohol effect central nervous system injury cytokine cytotoxic diabetic human NOS2A protein improved in vivo kinase inhibitor macrophage migration monocyte neuroinflammation neuron apoptosis neuropathology neuroprotection neurotoxic neurotoxicity oxidative damage prevent problem drinker protective effect reconstitution research study response rho virus development

项目摘要

DESCRIPTION (provided by applicant): Neuro-cognitive deficits observed in chronic alcoholics often mirror those in individuals with HIV-1-associated dementia (HAD). It has been suggested that alcohol abuse may serve as a co-factor in the development of HAD and exacerbate the symptoms of HIV-1 encephalitis (HIVE). We have previously shown that ethanol affects macrophage function (antigen presentation) and the blood brain barrier (BBS) by enhancing monocyte infiltration via disruption of tight junctions. We further demonstrated that the combined effects of alcohol abuse and HIV-1 infection affect adaptive immune responses and augment neuroinflammation in a small animal model of HIVE. These evidences support the idea that alcohol abuse is an exacerbating factor in HIV-1 central nervous system (CMS) infection through BBB damage and augmented neuroinflammation leading to neuronal injury and diminished anti-viral adaptive immunity. We propose that activation of peroxisome proliferator-activated receptor gamma (PPARgamma, an anti-inflammatory regulatory pathway) diminishes inflammatory cell activation in the CMS, alters their neurotoxic potential and renders protective effects. PPARgamma stimulation in endothelial cells can prevent monocyte transmigration to the brain in the setting of alcohol abuse and HIV-1 infection. In this competing continuation, we will investigate the therapeutic potential of PPARgamma activation and the mechanisms involved in PPARgamma-mediated amelioration of the combined deleterious effects of alcohol abuse by addressing the following questions: 1) Can PPARgamma stimulation alter the neuroprotective/neurotoxic potential of HIV-1-infected, immune activated macrophages [through cytokine and glutamate production, activation of inducible nitric oxide synthase and generation of reactive oxygen species, (ROS)]? 2) Can PPARgamma stimulation attenuate neuroinflammation by decreasing monocyte migration across the BBB (via up-regulation of ROS scavenging enzyme, superoxide dismutase)? And 3) Can PPARgamma agonists diminish neuroinflammation, improve BBB dysfunction and restore impaired immune responses associated with alcohol abuse in an animal model for HIVE? These studies will use cellular models, BBB constructs and an animal model for HIVE to mechanistically address putative protective effects of PPARgamma stimulation on BBB and neurons damaged by alcohol and interactions with HIV-1-infected macrophages. Since the last submission, we obtained additional data (namely significant anti-inflammatory and anti-viral effects of PPARgamma agonists) in support of the hypothesis being tested. The availability of PPARgamma agonists approved for clinical use will permit rapid translation of experimental findings into therapeutic applications.

描述（由申请人提供）：慢性酒精中毒中观察到的神经认知缺陷通常反映患有HIV-1相关痴呆症患者（HAT）的人。有人提出，酗酒可能是HAD和加剧HIV-1脑炎（Hive）的症状的共同因素。我们先前已经表明，乙醇通过通过破坏紧密连接的破坏来增强单核细胞浸润，从而影响巨噬细胞功能（抗原表现）和血脑屏障（BBS）。我们进一步证明，酒精滥用和HIV-1感染的综合作用会影响适应性免疫反应，并在蜂巢的小动物模型中增强神经炎症。这些证据支持这样一种观念，即酗酒是HIV-1中枢神经系统（CMS）通过BBB损伤和增强神经炎症导致神经元损伤和抗病毒适应性免疫的加剧因素。我们提出，过氧化物酶体增殖物激活的受体伽马（PPARGAMMA，一种抗炎调节途径）会减少CMS中炎症细胞激活，从而改变其神经毒性潜力并产生保护作用。内皮细胞中的ppargamma刺激可以防止在酒精滥用和HIV-1感染的情况下单核细胞转移到大脑。 In this competing continuation, we will investigate the therapeutic potential of PPARgamma activation and the mechanisms involved in PPARgamma-mediated amelioration of the combined deleterious effects of alcohol abuse by addressing the following questions: 1) Can PPARgamma stimulation alter the neuroprotective/neurotoxic potential of HIV-1-infected, immune activated macrophages [through cytokine and glutamate production, activation of可诱导的一氧化氮合酶和活性氧的产生，（ROS）]？ 2）PPARGAMMA刺激是否可以通过减少跨BBB的单核细胞迁移来减轻神经炎症（通过ROS清除酶，超氧化物歧化酶的上调）？ 3）ppargamma激动剂能否减少神经炎症，改善BBB功能障碍并恢复与蜂巢动物模型中与酒精滥用相关的免疫反应受损的受损？这些研究将使用细胞模型，BBB构建体和动物模型来机械地解决PPARGAMMA刺激对BBB的推定保护作用，以及受酒精损害以及与HIV-1感染的巨噬细胞相互作用的神经元的神经元。自上次提交以来，我们获得了其他数据（即ppargamma激动剂的显着抗炎和抗病毒作用），以支持被检验的假设。批准用于临床用途的ppargamma激动剂的可用性将允许将实验发现快速转化为治疗应用。