Pathogenesis of Endotoxin-Induced Acute Renal Failure

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My ultimate goal is to head an idependent research laboratory in an academic setting directed towards a better understanding of acute renal failure (ARF). I have spent the last three years of my nephrology fellowship investigating a mouse model of endotoxin-induced ARF is mediated by tumor necrosis factor (TNF) acting on its principal receptor, TNFRI, in kidney. This topic is highly relevant from a clinical perspective, as ARF is a common and serious syndrome with no effective therapy, and is frequently a consequence of sepsis. With the support of this Career Development Award, and the guidance and support of the University of Chicago's Section of Nephrology under the sponsorship of Dr. Richard Quigg, I hope to expand my skills into new areas such as cell biology, to advance towards this long-term goal. This proposal will test the hypothesis that endotoxin- induced ARF is a consequence of renal neutrophil infiltration, renal cell apoptosis, and other forms of neurotic or sublytic injury by the direct action of TNF on renal tubular cells. The first specific aim seeks to characterize the time course of leukocyte accumulation in the kidney after endotoxin administration, to identify key adhesion molecules and chemokines mediating this process, and to evaluate their pathogenic role with the use of inhibitory antibodies and genetic "knockout" mice. The second specific aim seeks to better characterize the time course of renal cell apoptosis after endotoxin administration and to evaluate its pathogenic role through the use of specific pharmacologic agents. The third specific aim seeks to describe the effects of TNF on renal proximal tubular cells in culture, and specifically to access their effects on cell viability, apoptosis, morphology, cell-cell adhesion, and metabolism. The fourth specific aim of this study seeks to characterize the renal hemodynamic effects which occur after the administration of endotoxin, specifically the effects on systematic blood pressure, renal blood flow, and renal vascular resistance. It is hoped that the answers to these scientific questions can be assembled into a overall paradigm of how endotoxin injures the kidney, and that this work can be translated into the design of effective therapies for ARF.