NEUROPROTECTION--INHIBITION OF OXIDATIVE STRESS

该申请建议创建“国家合作药物” 艾滋病毒感染治疗探索小组（NCDDG-HIV） Leon G博士的指导。罗切斯特大学的爱泼斯坦。的 拟议的NCDG-HIV的总体目标是阐明 参与HIV-1诱导的氧化应激（神经元）的机制， NFkB激活（在小胶质细胞和脑内皮细胞中）， 确定潜在的治疗靶点和化合物， 流程. 根据实验室的数据，研究人员 提出HIV-1感染的巨噬细胞和免疫激活的小胶质细胞 释放促炎物质，包括肿瘤坏死因子（TNF-α）。 α）、血小板活化因子（PAF）、花生四烯酸（AA）和毒性 病毒产物（gp 120，达特），其又引起（1）氧化应激 在神经元中，导致树突状细胞损伤，并最终死亡， 凋亡和（2）细胞转录的持续激活 NF κ B因子。 研究人员的目标是确定化合物， 阻断NFkB活化，抑制HIV-1复制 在小胶质细胞中，阻止HIV-1释放神经毒性产物， 感染和免疫激活的小胶质细胞，并保护神经元免于死亡 通过氧化应激导致细胞凋亡。

This application proposes the creation of a "National Cooperative Drug Discovery Group for the Treatment of HIV infection" (NCDDG-HIV) under the direction of Dr. Leon G. Epstein at the University of Rochester. The overall goal of the proposed NCDG-HIV is to elucidate t he critical mechanisms involved in HIV-1-induced oxidative stress (in neurons) and NFkB activation (in microglia and brain endothelial cells) in order to identify potential therapeutic targets and compounds that impact on these processes. Based on data from their laboratories, the investigators propose that HIV-1-infected macrophages and immune activated microglia release proinflammatory substances including tumor necrosis factor (TNF- alpha), platelet activating factor (PAF), arachidonic acid (AA), and toxic viral products (gp120, Tat) which in turn cause both (1) oxidative stress in neurons, resulting in dendritic damage and, ultimately, death by apoptosis and (2) persistent activation of the cellular transcription factor NFkB. The investigators goal is to identify compounds that share the properties of blocking NFkB activation, inhibiting HIV-1 replication in microglia, blocking the release of neurotoxic products from HIV-1- infected and immune-activated microglia, and protecting neurons from death via oxidative stress leading to apoptosis.