(Taken directly from the application) Polycystic kidney diseases (PKD) affect more than 500,000 people in the United States and are responsible for 10% of all patients receiving dialysis or transplantation for end-stage renal disease. The disease is characterized by the formation of multiple fluid-filled cysts that disrupt renal architecture and compromise normal renal function. Autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD) are genetic diseases caused by mutations in three known genes and several yet to be identified genes. The functions of the gene products are not known. It is widely accepted that there are changes in extracellular matrix, enhanced cell proliferation, and alterations in ion transport that accompany and/or drive cyst formation. The capacity of renal cystic epithelium to secrete fluid and the importance of EGF receptor overexpression and mislocalization have recently been established. The overall objective of this project to is to identify the ion transport phenotype of cystic epithelium, to establish the importance of C1 and fluid secretion in cyst expansion, and to determine the effect of EGFR signaling on collecting tubule ion transport in ARPKD. Our working hypothesis is that abnormal EGFR-signaling contributes to enhanced cell proliferation and unmasks a secretory phenotype in cystic epithelia. Electrophysiologic studies of renal slice organ culture, primary monolayer culture, and conditionally-immortalized cystic and non-cystic collecting tubule cell lines will be conducted. A pharmacologic and genetic approach will be used to evaluate the importance of amiloride-sensitive sodium absorption, barium-sensitive potassium secretion, and cAMP-or calcium-activated chloride secretion in cystic epithelia. The effect of apical and basolateral EFGR signaling on specific ion transport pathways will be evaluated. We anticipate that our findings with murine ARPKD will enhance our understanding of PKD cellular pathophysiology and contribute to the design of therapies for both autosomal recessive and autosomal dominant human PKD.
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