Characterization of the ciliary flow sensor and its role in epithelial cell polarity

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Disruption of primary cilia in the kidney leads to cyst formation, involving the loss of planar polarity. Increased proliferation and deregulated mTOR signalling. Exactly how this function is orchestrated by the ciliary flow sensor is difficult to examine in vivo and has not been clarified. Published data from our group using an in vitro approach suggests that two independent signalling pathways exist downstream of cilia, calcium and mTOR. Shear stress through fluid flow results in calcium transients involving the Pkd2 gene product TRPP2. Ciliary calcium signalling is required for the flow dependent orientation of centriole movements in the direction of flow. Independently of calcium, cilia under flow down-regulate the mTOR pathway specifically through the basal body. To improve the understanding of ciliary dysfunction in the pathogenesis of PKD, we aim to further dissect the control of these pathways downstream of cilia with the aim of gaining insight into the molecular control of polarity, proliferation and mTOR. Specifically we will study the role of the PKD1 gene product polycystin 1 in flow dependent mTOR regulation and analyze the role of other upstream mTOR regulators that have been associated with cystic disease such as TSC and Wnt. We will investigate the role of candidate proteins in flow induced polarity and analyze cell proliferation under flow with respect to cilia, the polycystins and components of the mTOR pathway.