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

肾脏初级纤毛的破坏导致囊肿形成，包括平面极性的丧失。增殖增加和mTOR信号转导失调。睫状流传感器如何精确地协调该功能难以在体内检查，并且尚未阐明。我们小组使用体外方法发表的数据表明，纤毛、钙和mTOR下游存在两种独立的信号传导途径。通过流体流动的剪切应力导致涉及Pkd2基因产物TRPP2的钙瞬变。纤毛钙信号传导是中心粒运动在流动方向上的流动依赖性取向所必需的。不依赖于钙，纤毛在流动下特异性地通过基体下调mTOR通路。为了提高对PKD发病机制中纤毛功能障碍的理解，我们的目标是进一步剖析纤毛下游这些通路的控制，目的是深入了解极性，增殖和mTOR的分子控制。具体来说，我们将研究PKD 1基因产物多囊蛋白1在流量依赖性mTOR调节中的作用，并分析与囊性疾病相关的其他上游mTOR调节因子（如TSC和Wnt）的作用。我们将研究候选蛋白在流动诱导极性中的作用，并分析流动下细胞增殖与纤毛、多囊蛋白和mTOR通路的组分的关系。

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.