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

• 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
• 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

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）：在慢性酗酒者中观察到的神经认知缺陷通常与 HIV-1 相关痴呆 (HAD) 患者的神经认知缺陷相似。有人认为，酗酒可能是 HAD 发展的辅助因素，并会加剧 HIV-1 脑炎 (HIVE) 的症状。我们之前已经证明，乙醇通过破坏紧密连接来增强单核细胞浸润，从而影响巨噬细胞功能（抗原呈递）和血脑屏障（BBS）。我们进一步证明，在 HIVE 小动物模型中，酗酒和 HIV-1 感染的综合影响会影响适应性免疫反应并增强神经炎症。这些证据支持这样的观点，即酗酒是 HIV-1 中枢神经系统 (CMS) 感染的加剧因素，通过 BBB 损伤和增强的神经炎症导致神经元损伤和抗病毒适应性免疫减弱。我们认为，过氧化物酶体增殖物激活受体γ（PPARγ，一种抗炎调节途径）的激活可以减少CMS中炎症细胞的激活，改变其神经毒性潜力并产生保护作用。在酗酒和 HIV-1 感染的情况下，内皮细胞中的 PPARgamma 刺激可以防止单核细胞迁移到大脑。在这个竞争性的延续中，我们将通过解决以下问题来研究 PPARgamma 激活的治疗潜力以及 PPARgamma 介导的改善酗酒综合有害影响的机制：1) PPARgamma 刺激能否改变 HIV 的神经保护/神经毒性潜力-1 感染、免疫激活的巨噬细胞 [通过细胞因子和谷氨酸的产生、诱导型一氧化氮合酶的激活和活性氧 (ROS) 的产生]？ 2) PPARgamma 刺激能否通过减少单核细胞跨 BBB 的迁移来减轻神经炎症（通过上调 ROS 清除酶、超氧化物歧化酶）？ 3) 在 HIVE 动物模型中，PPARgamma 激动剂能否减少神经炎症、改善 BBB 功能障碍并恢复与酗酒相关的受损免疫反应？这些研究将使用 HIVE 的细胞模型、BBB 构建体和动物模型来机械地解决 PPARgamma 刺激对 BBB 和因酒精损伤的神经元以及与 HIV-1 感染的巨噬细胞相互作用的假定保护作用。自上次提交以来，我们获得了额外的数据（即 PPARgamma 激动剂的显着抗炎和抗病毒作用）来支持正在测试的假设。批准用于临床的 PPARgamma 激动剂的可用性将允许将实验结果快速转化为治疗应用。