Neuroprotective role of NFKB in HIV dementia

NFKB 在 HIV 痴呆中的神经保护作用

• 批准号: 6659339
• 负责人: SANJAY B. MAGGIRWAR
• 金额: $ 26.66万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659339
• 关键词: AIDS dementia complex; RNase protection assay; cysteine endopeptidases; drug design /synthesis /production; genetic regulation; human immunodeficiency virus 1; laboratory rat; microarray technology; neuroprotectants; neurotoxins; nuclear factor kappa beta; tissue /cell culture

DESCRIPTION: (Provided by applicant): Severe neurologic complications, including HIV-associated dementia (HAD), occur in a significant proportion of HIV- 1 infected individuals. HAD is marked by cognitive and motor deficits, and pathologic correlates of this syndrome include neuronal apoptosis. Neuronal cell death and damage in HIV- 1 infected individuals are thought to be induced by a number of soluble neurotoxic factors, of both viral and cellular origin. Molecular pathways which may protect neurons from the deleterious effects of these candidate HIV-1 neurotoxins remain poorly understood. Preliminary data presented in this proposal show that the cellular transcription factor NFKB may protect neurons from the pro-apoptotic effects of candidate HIV- 1 neurotoxins. Our data further suggest that this may occur as a result of NFKB-mediated induction of genes, which negatively regulate programmed cell death. The experiments outlined in this proposal are intended to investigate the molecular mechanisms by which NFKB/Rel proteins exert their neuroprotective effects, and to determine the specific contribution of individual NFKB/Rel family members to this process. These studies will be conducted using well-characterized and appropriate neuronal model systems, and a representative array of candidate HIV-1 neurotoxins. Endogenous pathways of NFKB activation in neurons will also be examined, by using specific neurotrophins to activate this transcription factor, and a systematic investigation of NFKB-induced target genes will be performed, with an emphasis on genes involved in the regulation of apoptosis. Finally, the effects of NFKB activation on the caspase cascade will be examined, in neurons exposed to candidate HIV-1 neurotoxins, and in control cells. Taken together, these studies are expected to enhance our understanding of NFKB-mediated neuroprotection, and provide insights that may lead to the development of new therapeutic strategies for HIV-1 associated neurological disease.

描述：（由申请人提供）：严重的神经系统并发症， 包括 HIV 相关痴呆 (HAD)，在相当大比例的人群中发生 HIV-1 感染者。 HAD 的特点是认知和运动缺陷， 该综合征的病理相关性包括神经元凋亡。 HIV-1 感染者的神经元细胞死亡和损伤被认为 由许多可溶性神经毒性因子诱导，包括病毒和 细胞起源。可以保护神经元免受 这些候选 HIV-1 神经毒素的有害影响仍然很弱 明白了。该提案中提供的初步数据表明，蜂窝 转录因子 NFKB 可能保护神经元免受促凋亡作用 候选HIV-1神经毒素。我们的数据进一步表明这种情况可能会发生 作为 NFKB 介导的基因诱导的结果，该基因负向调节 程序性细胞死亡。本提案中概述的实验旨在 研究 NFKB/Rel 蛋白发挥作用的分子机制 神经保护作用，并确定具体贡献 各个 NFKB/Rel 家族成员参与此过程。这些研究将 使用特征良好且适当的神经元模型系统进行，以及 一系列具有代表性的候选 HIV-1 神经毒素。 神经元中 NFκB 激活的内源性途径也将通过以下方法进行检查： 使用特定的神经营养素来激活该转录因子，以及 对 NFKB 诱导的靶基因进行系统研究， 强调参与细胞凋亡调节的基因。最后， 将检查神经元中 NFKB 激活对 caspase 级联的影响 暴露于候选 HIV-1 神经毒素以及对照细胞中。综合起来， 这些研究有望增强我们对 NFKB 介导的理解 神经保护，并提供可能导致新疗法开发的见解 HIV-1相关神经系统疾病的治疗策略。