Tat, NADPH oxidase, and HIV-dementia

Tat、NADPH 氧化酶和 HIV 痴呆

• 批准号: 7066010
• 负责人: ANNADORA J BRUCE-KELLER
• 金额: $ 29.94万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7066010
• 关键词: AIDS dementia complex; JUN kinase; NAD(P)H dehydrogenase; astrocytes; behavior test; biological signal transduction; blood brain barrier; cellular pathology; collagenase; enzyme activity; enzyme induction /repression; genetically modified animals; glutamates; inflammation; laboratory mouse; microglia; mitogen activated protein kinase; neuropathology; neurotoxins; nuclear factor kappa beta; oxidative stress; superoxides; tissue /cell culture; transcription factor; tumor necrosis factor alpha; vascular endothelium permeability; virus protein

DESCRIPTION (provided by applicant): HIV dementia (HIVD) is a central nervous system complication of HIV viral infection that appears in as much as one fourth of AIDS patients. As HIV infection in the brain is relatively restricted, an unresolved issue in HIV research is how the low viral load in the brain causes such pronounced neuronal dysfunction. An intriguing possibility is that the deleterious effects of HIV infection in the brain are mediated by viral proteins, and a viral protein that has been repeatedly implicated in the pathogenesis of HIVD is the regulatory protein Tat. While it is not yet clear how Tat could cause the many manifestations of HIVD, recent data from our laboratory show that Tat is able to specifically increase NADPH oxidase-associated superoxide release and subsequent redox-based inflammatory signaling in glial cells, thereby driving toxic brain inflammation. Based on this data, we propose that Tat perturbs brain function by increasing both blood brain barrier breech and neuronal injury, and that these distinct pathways are mediated by a single mechanism: Tat-mediated induction of NADPH oxidase. To test this hypothesis, we have designed in vitro and in vivo studies making use of 2 novel mouse models of Tat-neurotoxicity to model HIVD. Specific aim 1 will test the hypothesis that Tat is able to significantly induce oxidative burst activity and redox-based signaling in astrocytes and microglial cells both in vitro and in vivo. Specific aim 2 will test the hypothesis that by directly triggering oxidative burst activity, Tat causes the release of matrix metalloproteinases and thus disrupts blood brain barrier integrity in mouse models of HIVD. Specific aim 3 will build upon these studies by testing the hypothesis that by increasing oxidative burst activity and redox signaling, Tat causes the release of neurotoxic inflammatory mediators (free radicals, excitotoxins and cytokines), culminating in neuronal injury and behavioral abnormalities in mice. Completion of these studies will result in a thorough understanding of the mechanisms of Tat-mediated neurotoxicity and could highlight a novel target for therapeutic intervention in HIVD.

描述（由申请人提供）：HIV痴呆（HIVD）是一种中枢神经系统的HIV病毒感染并发症，出现在艾滋病患者的四分之一中。由于大脑中的艾滋病毒感染相对受到限制，因此，艾滋病毒研究中未解决的问题是大脑的低病毒负荷如何引起这种明显的神经元功能障碍。一种有趣的可能性是，艾滋病毒感染在大脑中的有害作用是由病毒蛋白介导的，而病毒蛋白反复与HIVD的发病机理有关。虽然尚不清楚TAT如何引起HIVD的许多表现，但我们实验室的最新数据表明，TAT能够专门增加与NADPH氧化酶相关的超氧化物释放以及随后在神经胶质细胞中基于氧化还原的炎症信号传导，从而驱动有毒脑部炎症。基于这些数据，我们建议TAT通过增加血脑屏障臀位和神经元损伤来消除大脑功能，并且这些不同的途径是由单个机制介导的：TAT介导的NADPH氧化酶的诱导。为了检验这一假设，我们已经在体外和体内研究设计了2种新型的TAT神经毒性小鼠模型来建模HIVD。具体目标1将检验以下假设：TAT能够在体外和体内显着诱导星形胶质细胞和小胶质细胞中的氧化爆发活性和基于氧化还原的信号传导。特定目标2将检验以下假设：通过直接触发氧化爆发活性，TAT引起基质金属蛋白酶的释放，从而破坏HIVD小鼠模型中的血脑屏障完整性。 特定目标3将通过测试以下假说，即通过增加氧化爆发活性和氧化还原信号传导，TAT会导致神经毒性炎症介质（自由基，兴奋性毒素和细胞因子）的释放，在小鼠中导致神经元损伤和行为异常。这些研究的完成将导致对TAT介导的神经毒性的机制有深入的了解，并可以突出HIVD治疗干预的新靶标。