Novel Mechanism of Nephron Epithelialization

肾单位上皮化的新机制

• 批准号: 10253477
• 负责人: Rachel Katherine Miller
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253477
• 关键词: Actins; Biological; Cadherins; Cells; Childhood; Congenital Abnormality; Data; Defect; Development; Diagnosis; Embryo; End stage renal failure; Epithelial; Epithelial Attachment; Goals; Intercellular Junctions; Kidney; Mediating; Morphogenesis; Nephrons; Nutrient; Regenerative Medicine; Renal function; Research; Role; Testing; Urinary tract; Work; congenital anomaly; experimental study; insight; kidney malformation; nephrogenesis; nephron progenitor; novel; planar cell polarity; polymerization; prenatal; regenerative tissue; stem cells; treatment strategy; wasting

PROJECT SUMMARY/ ABSTRACT: NOVEL MECHANISM OF NEPHRON EPITHELIALIZATION (from original R01 proposal) 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that Daam1, a Wnt/ planar cell polarity effector, and Tuba (Dnmbp) are required for nephron morphogenesis, and unpublished data indicate that they are required for cell junction formation during epithelialization.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.

项目总结/摘要：肾单位上皮化的新机制 (from原R 01提案） 虽然先天性肾脏和泌尿道异常（CAKUT）是主要的出生缺陷， 在产前诊断，是儿童终末期肾病的最常见原因，仅 13%的病例有已知的单基因原因。CAKUT导致肾单位形成缺陷， 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如何 祖细胞形成细胞连接以促进小管上皮形成和形态发生。先前工作 表明Daam 1（Wnt/平面细胞极性效应子）和Tuba（Dnmbp）是肾单位 形态发生和未发表的数据表明，它们是细胞连接形成所必需的， 上皮化因此，本提案的目标是确定它们如何促进细胞连接的形成 肾单位祖细胞拟议的实验将测试Daam 1和Tuba使 在上皮形成和随后的发育中的形态发生过程中形成稳定的细胞连接 肾单位该假设将通过以下目标进行检验：目标1。评估Daam 1在 肾小管形成中细胞连接的建立。Daam 1介导的肌动蛋白 聚合调节钙粘蛋白介导的接触的形成，其促进肾上皮形成。 将测试小管。这一目标的实现将使人们深入了解以前未被认识到的 Daam 1在肾单位上皮形成中的作用。目标2.定义Tuba在细胞连接形成过程中的作用 肾发生拟议的实验将检验Tuba是上皮连接所需的假设 在发育中的肾单位中形成。这一目标的完成将揭示Tuba是否有助于连接 在上皮化肾单位中形成。总体而言，本申请中提出的实验将促进新的 了解有助于上皮形成和肾组织形态发生的细胞生物学机制， 小管