application) Cardiovascular disease and bacterial infections are the leading causes of death in patients with end-stage renal disease (ESRD) on hemodialysis (HD). Besides the high prevalence of well established risk factors, these patients are in a state of heightened oxidative stress, characterized by excessive free radical production and/or low antioxidant defenses. The principal hypothesis of this proposal is that exposure of polymorphonuclear cells to the dialysis membrane in the extracorporeal circuit, triggers production of reactive oxygen species (ROS) leading to increased apoptosis and phagocytic cell dysfunction, as well as oxidative endothelial cell injury. Furthermore, the increasingly routine use of parenteral iron, a potent promoter of toxic free radical generation, in these patients may enhance oxidative stress-induced cell injury and dysfunction. This proposal will address these concerns using in vitro models to evaluate the impact of dialysis membrane biocompatibility and various iron preparations on indices of oxidative stress, cell injury and apoptosis. These models will involve PMN (healthy vs. uremic) activation by exposure to dialysis membrane fragments of varying composition plus and minus iron or ROS inhibitors, as well as during circulation through an in vitro dialysis circuit. In addition, a co-culture model will be utilized to assess the effects of dialysis membrane-activated PMN on reporter monolayers of cultured human endothelial cells (plus and minus excess iron) grown under static and flow conditions. The results of this proposal are expected to enhance our understanding of the pathogenesis of ROS-induced cell injury and dysfunction and lay the foundation for the development of novel strategies to combat atherogenesis, vascular access and immune dysfunction in this vulnerable population. The Principal Investigator has designed a comprehensive series of studies to evaluate the hypotheses enunciated in this proposal, and is well qualified to carry them through to completion. In addition to a strong background in clinical nephrology, he has an established track record in laboratory research, and is the recipient of a Ph.D. He is mentored by investigators with extensive experience in laboratory research and advised by a panel of internationally renowned investigators in immune function, endothelial cell biology, free radical and antioxidant research. Within a limited time, he and his mentor have put together an infrastructure tailored to achieve the goals of this proposal. The practical experience from the research proposed, and the comprehensive education program outlined are expected to build on the candidate's current skills and experience, and facilitate his transition to an independent investigator in basic research in the field of nephrology.
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