Molecular Mechanisms Regulating Epithelial Cell Apical Polarity and Ciliogenesis

项目摘要 上皮细胞表现出显著的顶基底亚细胞极性，这是正常运作所必需的。 上皮组织，并允许上皮细胞形成特化的顶端结构，如顶端的初级纤毛。 最后，上皮细胞与相邻细胞协调极化，形成根尖管腔，这是 肾脏结构的建立，从而发挥其功能。因此，扰乱细胞功能的突变 根尖基底极化和根尖纤毛形成所需的分子会导致各种肾脏疾病， 如多囊肾病(PKD)。因此，这个项目的首要目标是描述 协调肾脏顶腔形成和纤毛发生的分子机制。为此，我们设计了 三个具体目标。在目标#1中，我们将分析、研究决定 以及顶腔何时形成以及如何与纤毛发生相协调。具体地说，我们将测试 新发现的极性调节因子Tbc1d1在肾脏发育过程中的调节作用。在 目的#2我们将剖析根尖管腔形成和初级纤毛形成/信号之间的协调。 我们最近鉴定了Rab19是Tbc1d1结合蛋白，并表明Rab19是纤毛所必需的 队形。因此，我们将研究Rab19在纤毛形成和纤毛驻留靶向中的作用。 蛋白质。最后，在目标#3中，我们将测试剖析介导肾瘤发生的机制和 斑马鱼体内纤毛发生。这个项目的完成将提供一个新的视角来理解 正常肾上皮细胞极化和纤毛形成的分子机制及调控 上皮组织形态发生和在疾病中。

Project Summary Epithelial cells exhibit remarkable apicobasal subcellular polarity that is essential for the proper functioning of epithelial tissues and allows epithelial cells to form a specialized apical structures, such as apical primary cilia. Finally, epithelial cells coordinate their polarization with neighboring cells to form an apical lumen, a key step in the establishment of renal architecture, and thereby function. Accordingly, mutations that disrupt function of molecules necessary for apicobasal polarization and apical cilia formation result in a variety of renal disorders, such as polycystic kidney disease (PKD). Thus, the overarching goal of this project is to characterize the molecular machinery coordinating apical lumen formation and ciliogenesis in kidney. To that end, we designed three specific aims. In the aim#1 we will analyze investigate the molecular machinery that determines where and when apical lumen forms and how that is coordinated with ciliogenesis. Specifically, we will test the role of newly identified polarity regulator Tbc1d1 in mediating lumenogenesis during kidney development. In the aim#2 we will dissect the coordination between the apical lumenogenesis and primary cilia formation/signaling. We recently identified Rab19 as Tbc1d1 binding protein and have shown that Rab19 is required for cilia formation. Thus, we will investigate the role of Rab19 in mediating cilia formation and targeting of cilia resident proteins. Finally, in aim#3 we will test dissect the mechanisms mediating kidney lumenogenesis and ciliogenesis in vivo using zebrafish. Completion of this project will provide a novel insight in understanding the molecular machinery and regulation of kidney epithelial cell polarization and cilia formation during normal epithelial tissue morphogenesis and in disease.