NEUROPROTECTION--INHIBITION OF OXIDATIVE STRESS

本申请书提出要创建国家药品合作组织 艾滋病毒感染治疗发现小组“(NCDDG-HIV) 罗切斯特大学利昂·G·爱泼斯坦博士的指导。这个 拟议的NCDG-HIV的总体目标是阐明关键的 HIV-1诱导(神经元)氧化应激的机制和 激活NFkB(在小胶质细胞和脑内皮细胞中)，以便 确定潜在的治疗靶点和化合物，以影响这些 流程。根据他们实验室的数据，调查人员 提示HIV-1感染的巨噬细胞和免疫激活的小胶质细胞 释放包括肿瘤坏死因子在内的促炎物质 α)、血小板激活因子(PAF)、花生四烯酸(AA)和毒性 病毒产物(gp120、tat)，进而导致(1)氧化应激 在神经元中，导致树突状细胞损伤，最终通过 细胞凋亡和(2)细胞转录的持续激活 因数NFkB。研究人员的目标是找出那些共有的化合物 阻断NFkB活化、抑制HIV-1复制的特性 在小胶质细胞中，阻止HIV-1神经毒性产物的释放- 感染和免疫激活的小胶质细胞，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.