Novel Role of Nephron Epithelialization in Nuclear Signaling

肾单位上皮化在核信号传导中的新作用

基本信息

批准号：
10587605
负责人：
Rachel Katherine Miller
金额：
$ 33.57万
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：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587605
关键词：
Actins Address Adherens Junction Adhesions Affect Area Attenuated Automobile Driving Biological Birth Cadherins Cell Communication Cell Nucleus Cells Childhood Complex Congenital Abnormality Data Defect Development Developmental Process Embryo End stage renal failure Epithelium Failure Funding Generations Genetic Genitourinary system Goals Grant Human Image Intercellular Junctions Kidney Kidney Transplantation Mediating Microfilaments Modeling Morphogenesis Nephrons Nuclear Pathologic Pathway interactions Polymers Population Process Proteins Quantitative Evaluations Regulation Renal function Renal tubule structure Research Role Signal Transduction Testing Urinary tract Vesicle WNT Signaling Pathway Work Xenopus beta catenin body system cell assembly congenital anomalies of the kidney experimental study improved in vivo insight malformation nephrogenesis nephron progenitor novel planar cell polarity polymerization stem cells working group

项目摘要

PROJECT SUMMARY/ABSTRACT: NOVEL ROLE OF NEPHRON EPITHELIALIZATION IN NUCLEAR SIGNALING Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of pediatric end- stage renal disease resulting in the need for kidney transplant. They occur in almost 2% of births, making up nearly one-fourth of all birth defects. However, only 14% of cases have a known genetic cause. Many CAKUT cases result from defects in the formation of nephrons, which are composed of epithelial tubules that are required for the proper function of the kidney. Prior studies indicate that disruption of either the planar cell polarity (PCP) pathway or exocyst vesicle complex result in malformation of the nephric tubules, indicating that these components are required for proper tubule formation. In our previous studies, we evaluated how tubulogenesis is facilitated through the PCP and exocyst complexes independently. We investigated distinct models by which Daam1, a formin protein that assembles actin filaments as part of the Wnt/planar cell polarity pathway, and Dnmbp/Tuba, which regulates exocytic vesicle targeting, facilitate tubulogenesis by promoting the generation of cell-cell contacts between nephron progenitor cells. We discovered a novel mechanism that utilizes the Wnt/PCP formin protein Daam1 to drive cell junction formation between nephron progenitor cells to generate tubules by polymerizing actin to stabilize cadherin at adherens junctions. Additionally, our results indicate that the exocyst-associated component Dnmbp facilitates the targeting of junctional components to initiate formation of these cell contacts between nephron progenitors. Despite this progress, we do not understand how the formation of cell-cell contacts influences the developmental processes of tubule epithelialization and morphogenesis in developing nephrons. To address this significant question, we will build upon on our important discoveries to evaluate how cell junction formation impacts the development of the nephric tubules by: 1) Identifying how the interaction between Daam1 and Dnmbp regulates cell-cell contact formation between nephron progenitors and 2) Determining whether Daam1’s role in junction formation regulates beta-catenin’s junctional versus Wnt signaling roles during nephrogenesis. Overall, the experiments proposed in this application will facilitate a new understanding of how cells interact and communicate to carry out tubulogenesis that has relevance in multiple organ systems. The quantitative evaluation of cell biological mechanisms involved in nephric development is a new area of study that will contribute valuable insights into epithelialization and morphogenesis mechanisms underlying tubulogenic processes.

项目概要/摘要：肾单位上皮化在核信号传导中的新作用先天性肾脏和泌尿道异常 (CAKUT) 是儿童终末期肾病的最常见原因，导致需要进行肾移植，其发生率接近 2%，占所有出生缺陷的近四分之一。然而，只有 14% 的病例有已知的遗传原因，许多 CAKUT 病例是由肾单位形成缺陷引起的，肾单位由上皮小管组成，是肾单位正常功能所必需的。先前的研究表明，平面细胞极性（PCP）途径或外囊泡复合物的破坏会导致肾小管畸形，这表明这些成分是肾小管正常形成所必需的。我们通过 PCP 和外囊复合物独立地研究了 Daam1 的不同模型，Daam1 是一种福尔明蛋白，可组装肌动蛋白丝作为 Wnt/平面细胞极性的一部分。我们发现了一种利用 Wnt/PCP 福明蛋白 Daam1 驱动肾单位之间细胞连接形成的新机制。此外，我们的结果表明，外囊相关成分通过聚合肌动蛋白来稳定粘附连接处的钙粘蛋白来产生小管。 Dnmbp 促进连接成分的靶向，以启动肾单位祖细胞之间这些细胞接触的形成，尽管取得了这一进展，但我们不了解细胞-细胞接触的形成如何影响发育中肾单位的肾小管上皮化和形态发生的发育过程。重要的问题，我们将在我们的重要发现的基础上，通过以下方式评估细胞连接形成如何影响肾小管的发育：1）确定 Daam1 和 Daam1 之间的相互作用如何Dnmbp 调节肾单位祖细胞之间的细胞-细胞接触形成，2) 确定 Daam1 在连接形成中的作用是否调节 β-连环蛋白在肾发生过程中的连接与 Wnt 信号传导作用。总体而言，本申请中提出的实验将有助于对细胞如何相互作用和形成的新理解。进行通信以进行与多个器官系统相关的肾小管发生，对肾发育中涉及的细胞生物学机制的定量评估是一个新的研究领域，它将提供有价值的见解。进入小管发生过程的上皮化和形态发生机制。