Delineating a role for non-canonical wnt signaling in PKD

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DESCRIPTION (provided by applicant): Despite the fact that they are some of the most common structures in biology, the precise molecular and cellular processes that regulate the formation of epithelial tubules are still unknown. Several recent studies have suggested planar cell polarity (PCP) contributes to the development and/or progression of various tubular diseases including polycystic kidney disease. However, it is still not clear how planar cell polariy is established or what effects it has on tubule development. Over the last several years, we have generated and characterized a number of genetic and chemical methods for perturbing and analyzing PCP in the mouse kidney. We have discovered that Wnt signaling is required for planar orientation of cells within the kidney tubular epithelium and that defects in this process are associated with cyst formation. However, we don't know why. We hypothesize that Wnt signaling mediates patterning of the stroma and that stromal signals establish PCP. Further, we hypothesize that oriented cell movement is required to establish and maintain the proper diameter of kidney tubules. In this proposal, we will use a combination of genetic engineering as well as live cell imaging to test these hypotheses as well as determining whether these processes are perturbed in orthologous models of PKD.