APOPTOSIS AND AIDS--ROLE OF TAT GENE

细胞凋亡与艾滋病--tAT基因的作用

• 批准号: 6289925
• 负责人: JAMES C. BARRETT
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289925
• 关键词: AIDS; apoptosis; cellular pathology; cytotoxicity; growth factor receptors; human immunodeficiency virus; human tissue; microorganism culture; nuclear factor kappa beta; oncogenes; oxidative stress; receptor expression; recombinant proteins; tumor necrosis factor alpha; tumor suppressor genes; virus genetics; virus protein

A number of mechanisms have been proposed to explain the depletion of helper CD4+ cells in HIV-infected individuals. This loss may be associated with increase apoptosis. Current studies in our laboratory are directed toward understanding the mechanisms employed by cells undergoing programmed cell death. We have focused on the role of the HIV tat gene in this process. Tat can modulate the redox state of cells by altering the activity of various enzymes to shift the cellular state toward pro-oxidant conditions. We have shown that the altered redox state can cause cells to die by apoptosis. Currently we are studying the regulation of the cell death mediated by the interactions of the tat andTNF-alpha as well as the role of p53 and oxidant stressors in the process. We have generated several cell lines that contain constitutively activated tat. In these cells, tat potentiated TNF- induced activation of the transcription factor, NF-kappa-B, and cellular cytotoxicity. In addition we have shown that TNF-induced toxicity is mediated by the TNFRI. Furthermore, we have shown that addition of recombinant, soluble HIV tat protein could induce TNFRI expression. By increasing TNFRI, tat is able to potentiate the effects of TNF. This is the final year for this project, some components of this project will be continued under a new project # involving cDNA microarrays. - apoptosis, tat, tumor necrosis factor, NF-kappa B, CAPE, oxidative stress

已经提出了许多机制来解释HIV感染者辅助CD4+细胞的耗尽。这种缺失可能与细胞凋亡增加有关。我们实验室目前的研究旨在了解经历细胞程序性死亡的细胞所使用的机制。我们重点研究了HIV Tat基因在这一过程中的作用。TAT可以通过改变各种酶的活性来调节细胞的氧化还原状态，从而将细胞状态转变为有利于氧化的状态。我们已经证明，氧化还原状态的改变可以导致细胞通过凋亡而死亡。目前，我们正在研究TAT和肿瘤坏死因子-α的相互作用对细胞死亡的调节，以及P53和氧化应激源在这一过程中的作用。我们已经产生了几个含有成分激活的TAT的细胞系。在这些细胞中，TAT增强了肿瘤坏死因子诱导的转录因子--核因子-kappa-B的激活，以及细胞的细胞毒性。此外，我们还证明了肿瘤坏死因子诱导的毒性是由TNFRI介导的。此外，我们还发现加入重组的、可溶的HIV Tat蛋白可以诱导TNFRI的表达。通过增加TNFRI，TAT能够增强肿瘤坏死因子的作用。这是该项目的最后一年，该项目的一些组成部分将在一个新的项目#下继续进行，该项目涉及基因芯片。-细胞凋亡，TAT，肿瘤坏死因子，核因子-kappaB，CAPE，氧化应激