Cellular effects of carbon monoxide

描述(申请人？S摘要)：本项目旨在调查 低浓度CO在大气中的作用机制 低氧可以解释新的初步数据显示它在 体内的细胞凋亡和细胞增殖或生长。尽管存在着 低氧，一氧化碳与氧化应激有关，表现为 线粒体谷胱甘肽，以及在肺中，锰的超氧化物增加 超氧化物歧化酶(MnSOD)和血红素加氧酶-1(HO-1)表达。此外, 一氧化碳暴露动物线粒体对三磷酸腺苷易化更敏感 渗透性转变，这使细胞对 线粒体通过释放细胞色素c启动细胞凋亡。这些 线粒体对mtDNA的降解也很敏感，但对mtDNA不敏感。 由外部氧化剂如叔丁基氢过氧化氢降解。这些数据 表明CO对线粒体造成了沉重的氧化/亚硝化负担。 我们认为，许多氧化负担与呼吸有关。 链，因为一氧化碳引起细胞色素的氧化还原(氧化还原)变化 B-C(L)地区。我们还假设，线粒体渗漏增加 过氧化氢为细胞提供氧化还原信号。因此，我们建议继续推行 一氧化碳诱导的线粒体氧化损伤机制的特异性AIMS 1和 2，并研究了具有氧化还原作用的CO激活信号转导机制 参与细胞凋亡和/或细胞增殖的特定反应元件 目标3和目标4。最后在目标5中，我们将调查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，该项目试图定义一个 通过检测细胞对CO的独特反应的生物学机制 一氧化碳相关氧化/亚硝化事件直接改变 线粒体通透性、氧化还原和合成功能及其对细胞的影响 通过这些机制传递信号和/或生存。

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.