Cellular effects of carbon monoxide

一氧化碳对细胞的影响

• 批准号: 7113719
• 负责人: CLAUDE A PIANTADES
• 金额: $ 4.85万
• 依托单位: DUKE UNIVERSITY
• 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/7113719
• 关键词: apoptosis; carbon monoxide; carbon monoxide poisoning; cell proliferation; cellular pathology; cellular respiration; cerebral ischemia /hypoxia; cytochrome c; heme oxygenase; hypoxia; laboratory rat; membrane permeability; mitochondria; nuclear factor kappa beta; oxidation reduction reaction; oxidative stress; oxygen tension; respiratory hypoxia; superoxide dismutase; tissue /cell culture

DESCRIPTION (Applicant?s Abstract): This project is designed to investigate mechanisms by which low concentrations of CO could exert effects during hypoxia that would explain new preliminary data showing it mediates both apoptosis and cell proliferation or growth in vivo. Despite the presence of hypoxia, CO is associated with oxidative stress as shown by depletion of mitochondrial glutathione, and in the lung, increases in manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1) expression. In addition, mitochondria from CO exposed animals are more sensitive ex vivo to ATP-facilitated permeability transition, which makes the cell more sensitive to mitochondrial initiation of apoptosis through cytochrome c release. These mitochondria are also susceptible to mtDNA degradation by NO, but not to mtDNA degradation by external oxidants such as t-butyl hydroperoxide. These data indicate that CO places a heavy oxidative/nitrosative burden on mitochondria. We propose that much of the oxidative burden is related to the respiratory chain because CO causes oxidation-reduction (redox) changes in the cytochrome b-c(l) region. We also hypothesize that increased mitochondrial leakage of H2O2 provides a redox signal to the cell. Therefore, we propose to pursue the mechanisms of CO-induced mitochondrial oxidant injury in Specific Aims 1 and 2, and investigate activation of mechanisms of signaling by CO that have redox response elements involved in apoptosis and/or cell proliferation in Specific Aims 3 and 4. Finally in Aim 5, we will investigate the possibility that HO-1, which produces CO endogenously, activates the same intracellular mechanisms associated with exogenous CO exposure. Thus, the project seeks to define a biological mechanism for the unique cellular responses to CO by testing the hypothesis that CO-related oxidative/nitrosative events directly alter mitochondrial permeability, redox and synthetic function and influence cell signaling and/or survival through these mechanisms.

描述（申请人？s摘要）：本项目旨在调查 低浓度的一氧化碳可以发挥作用的机制， 缺氧，这将解释新的初步数据显示，它介导 凋亡和细胞增殖或生长。尽管存在 缺氧，CO与氧化应激有关，如通过消耗 线粒体谷胱甘肽，在肺中，锰超氧化物增加 锰超氧化物歧化酶（MnSOD）和血红素氧合酶-1（HO-1）表达。此外，本发明还提供了一种方法， 来自CO暴露动物的线粒体离体对ATP促进的 渗透性转变，这使得细胞对 线粒体通过细胞色素c释放启动凋亡。这些 线粒体也易受NO降解，但对mtDNA不敏感 通过外部氧化剂如叔丁基过氧化氢降解。这些数据 表明CO对线粒体造成了严重氧化/亚硝化负担。 我们认为，大部分的氧化负荷与呼吸系统有关。 因为CO引起细胞色素中的氧化还原（氧化还原）变化 b-c（l）区域。我们还假设，增加线粒体渗漏， H2 O2向电池提供氧化还原信号。因此，我们建议， CO诱导的线粒体氧化损伤的机制在特定目的1和 2，并研究具有氧化还原的CO信号转导机制的激活 参与细胞凋亡和/或细胞增殖的特异性反应元件 目标3和4。最后，在目标5中，我们将研究HO-1， 内源性产生一氧化碳，激活相同的细胞内机制 与外源性一氧化碳暴露有关。因此，该项目旨在确定一个 通过测试CO的独特细胞反应的生物学机制， 假设CO相关氧化/亚硝化事件直接改变 线粒体通透性、氧化还原和合成功能，并影响细胞 信号和/或生存通过这些机制。