Congenital abnormalities of the kidney are the major cause of pediatric kidney disease which encompass renal agenesis, juvenile cystic disease, nephrotic syndromes, and Wilms tumor. Understanding kidney development not only guides our understanding of congenital kidney disease but also provides a framework for developing interventions to restore kidney function. Many known disease genes are transcription factors and signaling molecules that regulate kidney organogenesis;in this proposal we aim to understand how regulatory and signaling molecules function to drive initial formation of the kidney and how they might be harnessed to promote kidney tubule regeneration. We have discovered that the odd- skipped related1 (osr1) gene is required to regulate the development of all nephron cell types in zebrafish and for nephrogenesis in mice. We propose extending our comparative analysis of osr1 function in zebrafish and mouse to characterize a distinct cell-autonomous role for osr1 in podocyte differentiation and a non-cell autonomous role for osr1 in tubule cell and angioblast differentiation. Mosaic analysis of osr1-deficient cells in zebrafish embryos, knockdown approaches in mouse kidney explant culture, and generation of a conditional Osr1 knockdout mouse will be used to further our understanding of conserved functions of osr1 in kidney cell differentiation and nephron patterning. Cell non-autonomous effects of osr1-deficiency in zebrafish appear to be due to altered wnt signaling. We will examine wnt signaling and the function of frizzled receptors in previously unexplored contexts including nephric duct formation, nephron patterning, and recovery from kidney injury. Insights gained from this work will guide future efforts to direct kidney progenitor cell differentiation and restore kidney tubule function after injury.
Birth defects associated with impaired kidney development are the primary cause of pediatric kidney disease and can have long lasting effects into adulthood. Chronic kidney disease that results is currently only treatable by kidney dialysis or transplant. We aim to better understand kidney birth defects and apply what we learn about gene regulation and cell signaling to new approaches to treating pediatric and adult kidney disease.
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