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

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反映了hiv -1相关痴呆（HAD）患者的神经认知缺陷。有研究表明，酒精滥用可能是HAD发展的一个辅助因素，并加剧HIV-1脑炎（HIVE）的症状。我们之前的研究表明，乙醇通过破坏紧密连接增强单核细胞浸润，从而影响巨噬细胞功能（抗原呈递）和血脑屏障（BBS）。在HIVE的小动物模型中，我们进一步证明了酒精滥用和HIV-1感染的联合效应会影响适应性免疫反应并增加神经炎症。这些证据支持酒精滥用是HIV-1中枢神经系统（CMS）感染的一个加重因素，通过血脑屏障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。我们提出过氧化物酶体增殖体激活受体γ （PPARgamma，一种抗炎调节途径）的激活减少了CMS中炎症细胞的激活，改变了它们的神经毒性潜能，并产生了保护作用。在酒精滥用和HIV-1感染的情况下，内皮细胞中的PPARgamma刺激可以阻止单核细胞向大脑的迁移。在这篇竞争性的续篇中，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介导的酒精滥用综合有害影响的改善机制：1) PPARgamma刺激能否改变hiv -1感染、免疫激活的巨噬细胞的神经保护/神经毒性潜能[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) ppγ刺激是否可以通过减少单核细胞在血脑屏障上的迁移（通过上调活性氧清除酶、超氧化物歧化酶）来减轻神经炎症？3)在HIVE动物模型中，PPARgamma激动剂能否减轻神经炎症，改善血脑屏障功能障碍，恢复与酒精滥用相关的免疫反应受损？这些研究将使用细胞模型、血脑屏障构建和HIVE动物模型，从机制上解决pppargamma刺激对脑屏障和酒精损伤神经元的保护作用，以及与hiv -1感染的巨噬细胞的相互作用。自上次提交以来，我们获得了额外的数据（即PPARgamma激动剂的显著抗炎和抗病毒作用），以支持正在测试的假设。批准临床使用的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。

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.