Integrative Biology of Childhood Kidney Disease

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DESCRIPTION, OVERALL (provided by applicant): We propose to develop an interdisciplinary Research Center of Excellence in Pediatric Nephrology (RCEPN) at the Medical College of Wisconsin to delineate the underlying genetic and cellular causes of childhood renal disease and its progression. Such data are critical in developing specific therapies to prevent the initiation and progression of disease in the pediatric age group. Since childhood kidney disease is often a harbinger of renal and cardiovascular complications in adults, translational bench to bedside approaches have great promise. (Avner, E.D. and Kliegman, R.M.: Scientific Foundations of Clinical Practice, Part I and II, Pediatric Clinics of North America 53:559-806; 807-1051;2006 Vol I and 2). Kidney disease is a major cause of illness and death in infants, children and adolescence. Overall registry data from both the United States and Europe indicate that approximately 50% of all children have structural renal abnormalities, generally associated with known or suspected genetic mutations. Accordingly, a major project of the current application focuses on the genetic and cellular basis of normal and abnormal renal developmental biology in the etiology and progression of Polvcystic Kidney Disease. Major causes of acquired renal disease in childhood involve glomerular injury with subsequent alterations in renal vascular, hemodynamics and autoregulatory failure. The resultant hyperfiltration injury is a major cause of disease progression and tubulointerstitial fibrosis in diabetic nephropathy, focal segmental sclerosing glomerulonephritis, hypertension, and any primary renal disease which leads to nephron loss. Therefore, another major project of the RCEPN focuses on the genetic and metabolic determinants of altered renal hemodynamics in glomerular injury and progressive tubulointerstitial fibrosis. Interestingly, these two disparate areas may have common pathophysiological linkages through alterations in renal metabolism of arachidonic acid. The Biochemical and Mass Spectroscopy Core and the Genomic Animal and Vector Core directly support these projects, as well as supporting a robust pilot and feasibility (P & F) program which has selected four outstanding applications from an impressive initial applicant pool. These Pilot and Feasibility projects deal with specific aspects of the genetic and cellular biology of acute ischemic injury, and the genetic modulation and biochemical basis of structural renal disease and diabetic nephropathy. It cannot be overemphasized that appropriate focus on childhood renal disease will decrease the burden of adult renal disease with its attendant morbidity and mortality. Since the basic molecular and cellular mechanisms of the majority of pediatric kidney disorders are poorly understood, the establishment of this RCEPN is particularly timely. In addition, progression to ESRD often occurs when a primary disease processes has been thought to be adequately treated. Therefore, a clear aim of both projects of this proposed RCEPN is the development of therapies which prevent or modulate this progression.