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.
The goal of this project is to understand the molecular mechanisms coordinating epithelial cell polarization, apical lumen formation and ciliogenesis in kidney cells. During four previous funding cycles we have demonstrated that polarized endosome transport and cell division plays key roles in targeting proteins to the apical plasma membrane and identified the proteins that are required for this process. In this study we will identify the function and regulation of these polarity organizing proteins as well as their role in apical lumen formation and ciliogenesis during normal kidney development as well as in polycystic kidney disease (PKD).
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