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.
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