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

描述(申请人提供)：在慢性酗酒者中观察到的神经认知缺陷通常反映出艾滋病毒-1相关痴呆症(HAD)患者的神经认知缺陷。有人建议，酗酒可能是患HAD和加重HIV-1脑炎(HIVE)症状的辅助因素。我们之前已经证明，乙醇通过破坏紧密连接而增加单核细胞的渗透，从而影响巨噬细胞功能(抗原提呈)和血脑屏障(BBS)。我们进一步证明了酒精滥用和HIV-1感染的综合影响影响了获得性免疫反应，并在一个小型动物模型中增加了神经炎症。这些证据支持酒精滥用是HIV-1中枢神经系统(CMS)感染的加剧因素，其机制是血脑屏障损伤和加重的神经炎症导致神经元损伤和抗病毒获得性免疫功能减弱。我们认为，激活PPARGamma(一种抗炎调节通路)可减少CMS中炎性细胞的激活，改变其神经毒性潜力，从而发挥保护作用。在酒精滥用和HIV-1感染的背景下，内皮细胞中的PPAR伽马刺激可以防止单核细胞向脑内迁移。在这一竞争的继续中，我们将通过解决以下问题来研究PPAR伽马激活的治疗潜力以及PPAR伽马介导的改善酒精滥用的联合有害影响的机制：1)PPAR伽马刺激能否改变HIV-1感染的免疫激活的巨噬细胞的神经保护/神经毒性潜力[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物种的生成，(ROS)]？2)PPAR伽马刺激能否通过减少跨越血脑屏障的单核细胞迁移(通过上调ROS清除酶和超氧化物歧化酶)来减轻神经炎症？3)在蜂房动物模型中，PPARγ激动剂能否减轻神经炎症，改善血脑屏障功能障碍，并恢复与酒精滥用相关的受损的免疫反应？这些研究将使用细胞模型、BBB结构和蜂箱的动物模型，从机械上解决PPAR伽马刺激对酒精损伤的BBB和神经元的假定保护作用，以及与HIV-1感染的巨噬细胞的相互作用。自上次提交以来，我们获得了更多的数据(即PPARγ激动剂的显著抗炎和抗病毒作用)，以支持正在检验的假设。PPAR伽马激动剂被批准用于临床，这将使实验结果迅速转化为治疗应用。

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.