(Taken directly from the application) Ischemia/reperfusion injury (IRI) is a major contributor to the organ damage that results in acute renal failure, one of the major causes of morbidity and mortality in hospitalized patients in the United States. IRI results in part from an inflammatory response in tissue following a period of ischemia (anoxia resulting from decreased vascular perfusion of the organ). Many factors are involved in ischemia/reperfusion injury, but considerable data points to an important role for phagocytes, and particularly neutrophils, as agents of injury in the kidney as well as other organs. The Rac2 GTPase is an important transducer of signals from cell surface receptors in neutrophils, and mice deficient in Rac2 exhibit numerous defects in neutrophil functions, including chemotaxis, adhesion and production of reactive oxygen species. We therefore propose that Rac2 deficient mice, as a consequence of defective phagocyte function, will be protected against ischemia/reperfusion injury. We propose to test this hypothesis using an experimental model of ischemia/reperfusion injury in the mouse, and to test the relative contribution of reactive oxygen species to injury using mice that lack NADPH-dependent phagocyte oxidase activity. We will exploit recent advances in gene therapy and imaging technologies to image neutrophil dynamics in live animals whose myeloid cells have been labeled with green fluorescent protein. We will use this system to investigate the effect of ischemia/reperfusion on leukocyte trafficking and apply this method to understanding alterations in neutrophil dynamics that result in attenuated ischemia/reperfusion injury in several knockout mouse models. These studies will provide a better understanding of the clinically important phenomenon of ischemia/reperfusion injury, and provide new methods for testing potential therapeutic approaches.
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