The Role of Planar Cell Polarity Signals in Shaping Kidney Tubules

平面细胞极性信号在肾小管塑造中的作用

基本信息

批准号：
8508258
负责人：
Rachel Katherine Miller
金额：
$ 11.35万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508258
关键词：
Address Affect Amphibia Animals Architecture Cell Polarity Cell division Cells Cilia Cystic Kidney Diseases Data Defect Development Disease Docking Embryo Epithelial Epithelium Equilibrium Experimental Models Goals Human Image Imagery Kidney Kidney Diseases Knowledge Lead Life Link Maintenance Malignant Neoplasms Mammals Mediating Mesenchyme Methods Modeling Molecular Target Monomeric GTP-Binding Proteins Morphogenesis National Institute of Diabetes and Digestive and Kidney Diseases Nephroblastoma Nephronophthisis Nephrons Organ Outcome Pathogenesis Pathology Pathway interactions Physical condensation Play Polycystic Kidney Diseases Process Publications Publishing Rana Regulation Renal Cell Carcinoma Renal carcinoma Renal tubule structure Research Project Grants Research Support Role Shapes Signal Pathway Signal Transduction Strabismus Sum Surface Ectoderm System Techniques Testing Tissues Transgenic Animals Transgenic Organisms Tube Vision Work Xenopus Xenopus laevis Zebrafish base beta catenin cell motility cilium biogenesis directional cell innovation insight kinetosome neoplastic cell nephrogenesis novel research study

项目摘要

DESCRIPTION (provided by applicant): Formation of renal tubules in both mammals and amphibians requires Wnt pathways. In kidney, aberrant Wnt signaling has been linked to developmental pathologies such as Wilms tumor and cystic diseases, as well as with renal cell carcinoma. Recent studies from our group and others indicate that canonical (?-catenin- mediated) Wnt signaling is essential for induction of nephron development. Additionally, studies suggest that primary cilia are required for a switch from canonical to non-canonical Wnt signaling, and that defects in primary cilia formation or signaling lead to cystogenesis. Varied tissues undergoing morphogenesis employ non-canonical Wnt (PCP: "planar cell polarity") pathways to promote processes including cell polarization and cytoskeletal modulation. Deficiencies in non-canonical Wnt signaling, which contributes to PCP, underlie a number of developmental or later defects, such as polycystic kidney disease and nephronophthisis. Using Xenopus laevis (frog) embryos, supplemented in some contexts with embryos of Danio rerio (zebrafish), this proposal first assesses the roles of non-canonical Wnt PCP components in kidney tubule morphogenesis. Our hypothesis is that the PCP components Daam1, WGEF, Prickle and Strabismus are required for primary cilia formation, which is in turn required for nephric morphogenesis. Xenopus offers experimental advantages including the facile introduction of exogenous constructs to block or activate signaling pathways, rapid development and easy visualization of the forming kidney under the surface ectoderm. Second, using transgenic approaches, we will address in living animals the role of PCP/ non-canonical Wnt signals in shaping and moving cells that are undergoing/ contributing to kidney tubule morphogenesis. Finally, an over-expression screen will be performed to discover new regulators of tubule formation. Overall, this work is novel in assessing the roles of the PCP components in kidney development; in utilizing transgenic approaches in Xenopus laevis to visualize and/ or target kidney development in living embryos; and in performing an unbiased over- expression screen to reveal additional and likely novel components involved in kidney tubulogenesis. In sum, we will enhance our understanding of kidney morphogenesis, which is likely to be relevant to obtaining insights on later pathologies that arise in humans.

描述（由申请人提供）：哺乳动物和两栖动物中肾小管的形成需要WNT途径。在肾脏中，异常的Wnt信号传导与Wilms肿瘤和囊性疾病等发育病理以及肾细胞癌有关。我们小组和其他人的最新研究表明，典型的（？ - 蛋白蛋白介导的）Wnt信号对于诱导肾单位发育至关重要。此外，研究表明，从规范的WNT信号转换转换为一级纤毛，并且原发性纤毛形成或信号传导导致囊肿发生。经历形态发生的各种组织采用非规范WNT（PCP：平面细胞极性”）途径来促进包括细胞极化和细胞骨架调节的过程。有助于PCP的非典型WNT信号传导的缺陷是许多发育或更高后的缺陷，例如多囊性肾脏疾病和肾单位噬菌体。该建议使用Xenopus laevis（Frog）胚胎，在某些情况下用Danio Rerio（Zebrafish）的胚胎补充，该建议首先评估了非典型的Wnt PCP成分在肾小管形态发生中的作用。我们的假设是，原发性纤毛形成需要PCP成分DAAM1，WGEF，PRICKLE和Strabismus，这又是肾脏形态发生所需的。 Xenopus提供了实验优势，包括易于引入外源构造以阻止或激活信号通路，快速发育以及表面外胚层下形成肾脏的易于可视化。其次，使用转基因方法，我们将在活体动物中解决PCP/非典型WNT信号在正在经历/促进肾小管形态发生/有助于的塑形和移动细胞中的作用。最后，将执行一个过表达的屏幕，以发现小管形成的新调节剂。总体而言，这项工作是在评估PCP成分在肾脏发育中的作用方面的新颖。在利用爪蟾laevis中的转基因方法可视化和/或靶向肾脏的胚胎中；并在执行公正的过度表达屏幕时揭示了肾小管肾小管发生涉及的其他新成分。总而言之，我们将增强对肾脏形态发生的理解，这很可能与获得人类中后来的病理的见解有关。