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。有人认为，酗酒可能是HAD发展的辅助因素，并加剧了HIV-1脑炎（HIVE）的症状。我们以前已经表明，乙醇影响巨噬细胞的功能（抗原呈递）和血脑屏障（BBS）通过增强单核细胞浸润通过破坏紧密连接。我们进一步证明了酒精滥用和HIV-1感染的联合作用会影响适应性免疫反应，并增加HIVE小动物模型中的神经炎症。这些证据支持这样的观点，即酒精滥用是通过BBB损伤和增强的神经炎症导致神经元损伤和降低的抗病毒适应性免疫的HIV-1中枢神经系统（CMS）感染的加重因素。我们认为过氧化物酶体增殖物激活受体γ（PPARgamma，一种抗炎调节途径）的激活减少了CMS中的炎性细胞激活，改变了它们的神经毒性潜力，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刺激可以防止单核细胞迁移到大脑。在这一竞争性的延续中，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介导的酒精滥用联合有害作用的改善机制：1）PPARgamma刺激是否可以改变HIV-1感染的免疫激活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产生，诱导型一氧化氮合酶的激活和活性氧的产生，（ROS）]？2)PPARgamma刺激能否通过减少单核细胞穿过BBB的迁移（通过ROS清除酶，超氧化物歧化酶的上调）来减轻神经炎症？和3）在HIVE动物模型中，PPARgamma激动剂能否减轻神经炎症，改善BBB功能障碍并恢复与酒精滥用相关的受损免疫应答？这些研究将使用细胞模型、BBB构建体和HIVE动物模型，以机械地解决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推定保护作用。自上次提交以来，我们获得了额外的数据（即PPARgamma激动剂的显著抗炎和抗病毒作用），以支持正在检验的假设。批准用于临床使用的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。

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.