Alcohol Abuse and HIV-mediated Neurotoxicity

描述(由申请人提供)： 酗酒仍然是主要的健康问题之一，约有1400万美国人(占总人口的5%)遭受酗酒之苦。然而，据报道，在美国，艾滋病毒阳性者长期饮酒的流行率在29%到60%之间。鉴于几个实验室的新结果，越来越明显的是，酗酒有助于艾滋病毒复制、疾病进展和艾滋病毒相关痴呆症的发展。此外，酒精和艾滋病毒都是独立已知的神经毒性物质，但尚不确定它们在酒精中是否会产生协同作用。 成瘾的HIV-1阳性者会导致促炎性物质的产生增加。此应用程序旨在解决现有知识中的这一差距。我们将研究酒精和两种病毒毒素(HIV-1gp120和Tat，)对细胞因子和趋化因子产生、氧化应激标志物、细胞凋亡、PPAR-？在星形胶质细胞/神经元中，这些有害影响是否可以通过使用酒精代谢拮抗剂、病毒毒素特异性siRNAs和PPAR-？激动剂。这些体外研究将扩展到体内情况，将在HIV-1TAT和gp120转基因小鼠中研究长期饮酒的影响。这些小鼠将被用来评估细胞因子和趋化因子的表达，脑内神经元的凋亡以及血脑屏障的渗漏，以及是否使用酒精拮抗剂和PPAR-？激动剂将消除酒精介导的神经毒性。

DESCRIPTION (provided by applicant): Alcohol abuse remains one of the major health problems with approximately 14 million Americans (<5% of total population) suffering from alcohol abuse. However, the prevalence of chronic alcohol consumption among HIV-positive individuals has been reported to be between 29 and 60% in US. In view of emerging results from several laboratories, it is becoming clear that alcohol abuse contributes to HIV replication, disease progression and development of HIV-associated dementia. Furthermore both alcohol and HIV are independently known to be neurotoxic, but it is not known with certainty whether they will have synergistic effect in alcohol addicted HIV-1 positive individuals and cause increased production of proinflammatory. This application is designed to address this gap in the existing knowledge. We will study the combined effect of the alcohol and 2 virotoxins (HIV-1 gp120 and Tat,) on cytokine as well chemokine production, markers of oxidative stress, apoptosis, PPAR-? in astrocytes/neurons, and whether these detrimental effects can be abrogated by use of the antagonists of alcohol metabolism, the virotoxin-specific siRNAs and PPAR-? agonists. These in vitro studies will be extended to in vivo situation where effect of chronic alcohol consumption will be studied in HIV-1 Tat and gp120 transgenic mice. These mice will be used for assessment of cytokine and chemokine expression, neuronal apoptosis in brain as well as leakage in the blood brain barrier and whether use of alcohol antagonist and PPAR-? agonists will abrogate the alcohol-mediated neurotoxicity.