Novel Mechanism of Nephron Epithelialization

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PROJECT SUMMARY/ ABSTRACT: NOVEL MECHANISM OF NEPHRON EPITHELIALIZATION (from original R01 proposal) Although congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant birth defects diagnosed in the prenatal period and are the most common cause of pediatric end stage renal disease, only 13% of cases have a known monogenic cause. CAKUT results in defects in the formation of nephrons, which are required for the function of the kidney. Thus, the overall goal this research is to understand how nephron progenitor cells form cell junctions to facilitate tubule epithelialization and morphogenesis. Prior work demonstrates that Daam1, a Wnt/ planar cell polarity effector, and Tuba (Dnmbp) are required for nephron morphogenesis, and unpublished data indicate that they are required for cell junction formation during epithelialization. Thus, the goal of this proposal is to determine how they facilitate cell junction formation in the nephron progenitor cells. The proposed experiments will test the hypothesis that Daam1 and Tuba enable the formation of stable cell junctions during epithelialization and subsequent morphogenesis of the developing nephrons. The hypothesis will be tested through the following aims: Aim 1. Assess the role of Daam1 in the establishment of cell junctions underlying nephric tubulogenesis. The hypothesis that Daam1-mediated actin polymerization regulates the formation of cadherin-mediated contacts that facilitate epithelialization of nephric tubules will be tested. Completion of this aim will provide insight into the previously unrecognized role of Daam1 in nephron epithelialization. Aim 2. Define the role of Tuba in cell junction formation during nephrogenesis. The proposed experiments will test the hypothesis that Tuba is required for epithelial junction formation in the developing nephron. Completion of this aim will uncover whether Tuba facilitates junction formation in epithelializing nephrons. Overall, the experiments proposed in this application will facilitate a new understanding of the cell biological mechanisms contributing to epithelialization and morphogenesis of nephric tubules.