NOVEL MECHANISM OF NEPHRON EPITHELIALIZATION

肾单位上皮化的新机制

基本信息

批准号：
9908069
负责人：
Rachel Katherine Miller
金额：
$ 23.25万
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 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908069
关键词：
Actins Adherens Junction Adhesions Affect Biological CRISPR/Cas technology Cadherins Cells Childhood Chronic Kidney Failure Complex Congenital Abnormality Cyst Data Defect Development Diagnosis Doctor of Medicine Doctor of Philosophy E-Cadherin Embryo End stage renal failure Epithelial Epithelial Attachment Epithelial Cells Epithelium Genes Goals Human Image Intercellular Junctions Kidney Maintenance Mediating Mesenchymal Stem Cells Microscopy Morphogenesis Morphology Mus Mutation Nephrons Nutrient Pathway interactions Patients Positioning Attribute Process Proteins Publishing Rana Regenerative Medicine Regulation Renal function Reproducibility Research Resolution Role Shapes Site Testing Time Tissues Urinary tract Vesicle WNT Signaling Pathway Work Xenopus base beta catenin congenital anomaly experimental study genome editing insight kidney malformation loss of function nephrogenesis novel planar cell polarity polymerization prenatal progenitor stem cells trafficking treatment strategy wasting

项目摘要

PROJECT SUMMARY/ ABSTRACT: NOVEL MECHANISM OF NEPHRON EPITHELIALIZATION Although congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant birth defects diagnosed in the prenatal period and are the most common cause of pediatric end stage renal disease, only 13% of cases have a known monogenic cause. CAKUT results in defects in the formation of nephrons, which are required for the function of the kidney. Thus, the overall goal this research is to understand how nephron progenitor cells form cell junctions to facilitate tubule epithelialization and morphogenesis. Prior work demonstrates that Daam1, a Wnt/ planar cell polarity effector, and Tuba (Dnmbp) are required for nephron morphogenesis, and unpublished data indicate that they are required for cell junction formation during epithelialization. Thus, the goal of this proposal is to determine how they facilitate cell junction formation in the nephron progenitor cells. The proposed experiments will test the hypothesis that Daam1 and Tuba enable the formation of stable cell junctions during epithelialization and subsequent morphogenesis of the developing nephrons. The hypothesis will be tested through the following aims: Aim 1. Assess the role of Daam1 in the establishment of cell junctions underlying nephric tubulogenesis. The hypothesis that Daam1-mediated actin polymerization regulates the formation of cadherin-mediated contacts that facilitate epithelialization of nephric tubules will be tested. Completion of this aim will provide insight into the previously unrecognized role of Daam1 in nephron epithelialization. Aim 2. Define the role of Tuba in cell junction formation during nephrogenesis. The proposed experiments will test the hypothesis that Tuba is required for epithelial junction formation in the developing nephron. Completion of this aim will uncover whether Tuba facilitates junction formation in epithelializing nephrons. Overall, the experiments proposed in this application will facilitate a new understanding of the cell biological mechanisms contributing to epithelialization and morphogenesis of nephric tubules.

项目摘要/摘要：肾单位上皮化的新机制尽管先天性肾脏和泌尿道异常 (CAKUT) 是产前诊断的主要出生缺陷，也是儿科终末期肾病的最常见原因，但只有 13% 的病例具有已知的单基因原因。 CAKUT 会导致肾单位形成缺陷，而肾单位是肾脏功能所必需的。因此，本研究的总体目标是了解肾单位祖细胞如何形成细胞连接以促进肾小管上皮化和形态发生。先前的工作表明，Daam1（一种 Wnt/平面细胞极性效应器）和 Tuba (Dnmbp) 是肾单位形态发生所必需的，未发表的数据表明它们是上皮化过程中细胞连接形成所必需的。因此，该提案的目标是确定它们如何促进肾单位祖细胞中的细胞连接形成。拟议的实验将验证 Daam1 和 Tuba 能够在上皮化和发育中肾单位随后的形态发生过程中形成稳定的细胞连接的假设。该假设将通过以下目标进行检验：目标 1. 评估 Daam1 在肾小管发生细胞连接建立中的作用。 Daam1 介导的肌动蛋白聚合调节钙粘蛋白介导的接触的形成，从而促进肾小管上皮化，这一假设将得到检验。这一目标的完成将有助于深入了解 Daam1 在肾单位上皮化中先前未被认识的作用。目标 2. 明确 Tuba 在肾发生过程中细胞连接形成中的作用。拟议的实验将检验以下假设：发育中的肾单位中上皮连接的形成需要大号。这一目标的完成将揭示 Tuba 是否促进上皮化肾单位的连接形成。总体而言，本申请中提出的实验将有助于对有助于肾小管上皮化和形态发生的细胞生物学机制有新的理解。