NOVEL MECHANISM OF NEPHRON EPITHELIALIZATION

项目总结/摘要：肾单位上皮化的新机制 虽然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导致肾单位形成缺陷，肾单位是肾功能所需的。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，Daam 1，Wnt/平面细胞极性效应子，和Tuba（Dnmbp）是肾单位形态发生所需的，未发表的数据表明，它们是上皮形成过程中细胞连接形成所需的。因此，本提案的目标是确定它们如何促进肾单位祖细胞中细胞连接的形成。拟议的实验将测试的假设，Daam 1和Tuba使形成稳定的细胞连接在上皮化和随后的形态发生的发展肾单位。该假设将通过以下目标进行检验：目标1。评估Daam 1在肾小管形成基础的细胞连接建立中的作用。Daam 1介导的肌动蛋白聚合调节钙粘蛋白介导的接触，促进肾小管上皮形成的假设将被测试。这一目标的完成将提供深入了解以前未被认识的作用Daam 1在肾单位上皮化。目标2.明确Tuba在肾发生过程中细胞连接形成中的作用。所提出的实验将检验Tuba是发育中的肾单位中上皮连接形成所需的假设。这一目标的完成将揭示Tuba是否有助于上皮化肾单位的连接形成。总之，本申请中提出的实验将有助于对肾小管上皮形成和形态发生的细胞生物学机制的新理解。

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that Daam1, a Wnt/ planar cell polarity effector, and Tuba (Dnmbp) are required for nephron morphogenesis, and unpublished data indicate that they are required for cell junction formation during epithelialization.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.