Molecular Mechanisms Regulating Epithelial Cell Apical Polarity and Ciliogenesis

调节上皮细胞顶端极性和纤毛发生的分子机制

基本信息

批准号：
10207607
负责人：
Rytis Prekeris
金额：
$ 33.76万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207607
关键词：
3-Dimensional Address Apical Architecture Binding Binding Proteins Biochemical Biochemistry Biological Assay Cell Culture Techniques Cell division Cell membrane Cells Cellular biology Cilia Complex Cues Cytokinesis Data Development Disease Docking Endosomes Epithelial Epithelial Cells Event Exhibits Funding Goals Homeostasis In Vitro Kidney Kidney Diseases Laboratories Location Mediating Modeling Molecular Morphogenesis Mutation Organogenesis Pathogenesis Play Polycystic Kidney Diseases Process Property Proteins Publishing Regulation Renal function Role Signal Transduction Site Structure Testing Tissues Transmembrane Transport Vertebral column Work Zebrafish base cilium biogenesis design imaging approach in vivo insight kidney cell kidney epithelial cell kinetosome mutant nephrogenesis novel polarized cell protein transport receptor tissue culture

项目摘要

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.

项目摘要上皮细胞表现出显着的apicobasal亚细胞极性，这对于正确功能至关重要上皮组织，并允许上皮细胞形成专门的顶端结构，例如顶端原发性纤毛。最后，上皮细胞与相邻细胞协调其极化以形成顶端管腔，这是一个关键步骤建立肾脏建筑，从而起作用。因此，破坏功能的突变腹骨偏振和顶端纤毛形成所需的分子导致多种肾脏疾病，例如多囊性肾脏疾病（PKD）。因此，该项目的总体目标是表征分子机制协调肾脏中的顶腔形成和纤毛发生。为此，我们设计了三个具体目标。在目标＃1中，我们将分析研究确定何处的分子机械当顶端腔形成以及如何与纤毛发生配合时。具体来说，我们将测试新鉴定的极性调节剂TBC1D1在肾脏发育过程中介导腔内作用中。在 AIM＃2我们将剖析根尖的腔内生成和原发性纤毛形成/信号传导之间的配位。我们最近将RAB19确定为TBC1D1结合蛋白，并表明cilia需要Rab19 形成。因此，我们将研究Rab19在介导纤毛形成和靶向纤毛居民中的作用蛋白质。最后，在AIM＃3中，我们将测试介导肾脏发光发生的机制和使用斑马鱼在体内的纤毛发生。该项目的完成将提供一个新颖的见解，以理解肾上皮细胞极化和纤毛形成的分子机制和调节上皮组织形态发生和疾病。