TOXIC AND THERAPEUTIC EFFECTS OF OXYGEN

此申请是为研究关系的计划项目拨款而申请的 分子氧、活性氧(ROS)之间的细胞水平 和一氧化氮(NO.)在生理和病理条件下。 决定氧的命运并调节其相互作用的因素 没有。组织硫醇池是这四个人的研究主题 构成建议书的项目。 项目1，一氧化碳期间和之后大脑代谢的研究 (CO)低氧，提示线粒体ROS的产生在不同的 大脑区域是神经元损伤的重要来源。这个 研究人员将把ROS的产生与兴奋性毒性的变化联系起来，NO。 生产和氧气利用率。ROS生产，包括NO.生产 将与神经病理和功能的变化相关联，以更好地 了解它们在神经元损伤中的作用。 下一个项目研究一氧化氮在细胞内的作用。 肺部呼吸道的生物化学。它解决了一个重大的悖论 肺，即NO的生物活性。与以下内容冲突 它在富氧环境中的既定毒性。关于这个问题的答案 人们将以NO的身份来寻找明显的悖论。要经历 决定加合物形成的氧化还原反应 蛋白质硫醇部分分布在细胞外和细胞内。 蛋白质硫醇NO.加合物，或S-亚硝硫醇，对 与分子氧反应，具有很强的生物活性。 项目3将评估分离的内皮细胞对一氧化氮的反应 氧化物。NO与多种细胞因子相互作用的作用机制 细胞靶点，将通过糖酵解酶GAPDH进行研究。 努力还将集中在NO的机制上。血管内皮细胞的形成 细胞，对NO的调节。形成，以及长期暴露的影响 细胞的数量减少到NO。重点是细胞蛋白质硫醇库的变化。 最后一个项目将评估细胞外超氧化物的作用。 超氧化物歧化酶(EC-SOD)对肺血管和气道功能的调节作用。它是 基于这一重要发现，EC-SOD是高度结构性的 在肺中表达，已定位于细胞外空间 在呼吸道和肺血管中的平滑肌细胞周围。这个 将验证EC-SOD是NO的关键生物调节因子的假说。 活动。EC-SOD和NOS。会在几个组织中共同定位 EC-SOD、O2、NO的功能关系。将在中进行探索 包括呼吸道和血管结构。

This application is for a Program Project Grant to study relationships at the cellular level between molecular oxygen, reactive oxygen species (ROS) and nitric oxide (NO.) under physiological and pathological conditions. Factors that determine the fate of oxygen and regulate its interactions with NO. and tissue thiol pools is the investigative theme for the four projects that comprise the proposal. Project 1, a study of brain metabolism during and after carbon monoxide (CO) hypoxia, proposes that mitochondrial ROS generation in different brain regions is a significant source of neuronal injury. The investigators will relate ROS production to changes in excitotoxicity, NO. production and O2 availability. ROS production including NO. production will be correlated with changes in neuropathology and function to better understand their roles in neuronal injury. The next project studies the role of nitric oxide in the cellular biochemistry of the airways of the lungs. It addresses a major paradox in the lung, i.e., that the biological activity of NO. is in conflict with its established toxicity in an oxygen-rich environment. Answers to this apparent paradox will be sought in the capacity of NO. to undergo oxidation-reduction reactions that determine the formation of adducts with protein thiol moieties located both extracellularly and intracellularly. Protein thiol NO. adducts, or S-nitrosothiols, which are resistant to reactions with molecular oxygen, possess potent biological activity. Project 3 will evaluate responses of isolated endothelial cells to nitric oxide. The mechanisms of action of NO., which interacts with a variety of cellular targets, will be investigated via the glycolytic enzyme, GAPDH. Efforts also will focus on mechanisms of NO. formation in endothelial cells, regulation of NO. formation, and the effects of prolonged exposure of cells to NO. with emphasis on changes in cellular protein thiol pools. The last project will evaluate the role of extracellular superoxide dismutase (EC-SOD) in modulating lung airway and vascular function. It is based on the important finding that EC-SOD, which is highly constitutively expressed in the lungs, has been localized in the extracellular spaces around smooth muscle cells in airways and in pulmonary vasculature. The hypothesis will be tested that EC-SOD is a key bioregulator of NO. activity. Both EC-SOD and NOS. will be colocalized in several tissues and the functional relationships of EC-SOD, O2 and NO. will be explored in both airway and vascular structures.