Toxic and Therapeutic Effects of Oxygen

描述（申请人摘要） 此申请是一个计划项目的竞争性更新建议 资助研究组织变化的生理和病理影响， 与活性氧（ROS）相关的细胞氧浓度 以及两种气体信号分子一氧化氮的作用机制 (NO)和一氧化碳（CO）。氧依赖过程对 完整的细胞和组织，以及它们与NO和CO的相互作用 参与细胞内稳态和功能是共同的主题， 四个项目组成了该计划。 项目1是一项研究的细胞机制，CO在肺，脑和 血管组织在环境相关浓度下发挥作用 的气体。该项目的目的是检验假设， 细胞内对CO的反应主要通过其对 通过线粒体改变氧化剂产生的血红素蛋白。CO的影响 影响细胞的氧化还原（redox） 参与程序性细胞死亡（凋亡）和细胞凋亡的反应 增殖，特别是在肺和脑中的细胞缺氧期间。 项目6研究了血红蛋白之间的化学相互作用的作用， (Hb)分子和NO对肺血管反应的调节。 该提案将检验变构环境决定 Hb是否具有储存Fe（II）NO-Hb、消耗Fe（III）-Hb +硝酸盐或 通过SNO-Hb传递NO生物活性。项目6还将确定SNO-Hb是否 有效地对抗完整肺中的缺氧性肺血管收缩。 项目3研究了NO影响隔离适应的能力。 血管细胞的炎症和环境压力。该项目将 测试一氧化氮诱导血管细胞适应性反应的假设 通过基于谷胱甘肽的MAP激酶信号的氧化还原调节发生 信号通路包括ERK 1/2、p38、SAPK（JNK）和ERK 5。 项目7研究了细胞外ROS产生在全球范围内的作用。 小鼠脑缺血。该项目将测试假设， 细胞外超氧化物歧化酶（ECSOD）提供了有益的效果， 清除超氧阴离子（O2-）对缺血性脑损伤的影响 由活化的中性粒细胞、小胶质细胞或 膜结合氧化酶。

DESCRIPTION (Applicant's Abstract) This application is a proposal for a competitive renewal of a Program Project Grant to study physiological and pathological impact of changes in tissue and cellular oxygen concentration as they relate to reactive oxygen species (ROS) and the mechanisms of action of two gaseous signaling molecules, nitric oxide (NO) and carbon monoxide (CO). The effects of oxygen dependent processes on intact cells and tissues, and their interactions with NO and CO as they are involved in cellular homeostasis and function are the common theme for the four projects that comprise the program. Project 1 is a study of cellular mechanisms by which CO in lung, brain and vascular tissues exerts its effects at environmentally relevant concentrations of the gas. The objective of the project is to test the hypothesis that the intracellular responses to CO are mediated primarily through its effects on hemoproteins that alter oxidant production by mitochondria. The effects of CO on mitochondria are proposed to influence cellular oxidation-reduction (redox) reactions involved in programmed cell death (apoptosis) and cellular proliferation, particularly during cellular hypoxia in the lung and brain. Project 6 studies the role of chemical interactions between the hemoglobin (Hb) molecule and NO on the regulation of vascular responses in the lungs. The proposal will test the hypothesis that the allosteric environment dictates whether Hb functions to store Fe(II)NO-Hb, consume Fe(III)-Hb + nitrate or deliver NO bioactivity via SNO-Hb. Project 6 will also determine whether SNO-Hb effectively opposes hypoxic pulmonary vasoconstriction in the intact lung. Project 3 investigates the ability of NO to influence adaptation of isolated vascular cells to inflammatory and environmental stresses. The project will test the hypothesis that NO--induced adaptive responses in vascular cells occur through glutathione-based redox regulation of MAP kinase signaling pathways including ERK1/2, p38, SAPK (JNK) and ERK5. Project 7 investigates the role of extracellular ROS production in global cerebral ischemia in mice. The project will test the postulate that extracellular superoxide dismutase (ECSOD) provides a beneficial effect on ischemic brain injury by scavenging superoxide anion (O2-) in the extracellular space generated either by activated neutrophils, microglia or membrane bound oxidases.