Autosomal dominant polycystic kidney disease (ADPKD): The role of Aurora kinase A (AURKA), NEDD9 and SRC in renal cystogenesis

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Autosomal dominant polycystic kidney disease (ADPKD) affects between 1:400 and 1:1000 individuals worldwide and typically manifests in middle age, with affected individuals progressing towards end stage renal disease. To date no specific treatment has been proven to prevent or delay ADPKD, although there are a number of emerging treatment strategies in PKD, currently in preclinical or clinical testing. ADPKD arises from mutations in PKD1 (~85% of cases) or PKD2 (~15% of cases) encoding polycystin-1 (PC1) and polycystin-2 (PC2). Their impaired function typically results in reduced intracellular Ca2+ pools, altered cell signaling by PC1- and PC2-interacting and effector proteins, loss of epithelial cell polarity, and deregulated renal cell growth. Beyond mutations in the PKD1 and PKD2 genes, mutations causing loss of primary cilia, which induces defects in sensing of external mechanosensory and soluble cues, again deregulating renal cell growth. Recently, important roles for AURKA, NEDD9 and SRC as regulators of ciliary integrity, PC2 activity, intracellular Ca2+ responses, and additional signaling relevant to ADPKD pathology has been established. In the described project the hypothesis will be tested that 1) abnormal function of AURKA, NEDD9 and SRC are linked and common in cystogenesis, and 2) targeted therapies focused on AURKA and SRC may have value in PKD contingent on NEDD9 status. Therefore the effect of a Nedd9-/- genotype on cystogenesis in mouse models for the conditional ablation of Pkd1 and Pkd2 will be analyzed. Further the interactions between NEDD9, AURKA, and SRC in signaling pathways relevant to cystogenesis will be dissected in renal cell lines and finally AURKA inhibitors in restricting cyst formation will be evaluated. The overall goal of this proposal is to better understand the interrelated functions of NEDD9 and its interaction partners AURKA and SRC kinase, both as a way of yielding fundamental insight into basic biology of PKD, and with the goal of suggesting new and accessible therapeutic strategies.