Novel Mechanism of Nephron Epithelialization

项目摘要/摘要：棉结上皮化的新机制 (摘自原R01提案) 虽然先天性肾和尿路畸形(CAKUT)是主要的出生缺陷 在产前被诊断，是儿童终末期肾脏疾病的最常见原因，仅 13%的病例有已知的单基因病因。CAKUT导致肾单位的形成缺陷，这是 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是如何 祖细胞形成细胞连接，促进小管上皮化和形态发生。前期工作 证明肾单位需要一个Wnt/平面细胞极性效应因子Daam1和Tuba(Dnmbp) 形态发生，以及未发表的数据表明，它们是细胞连接形成所必需的 上皮化。因此，这项建议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。拟议的实验将检验这样的假设：Daam1和Tuba使 上皮化过程中稳定的细胞连接的形成以及随后发育中的形态发生 尼弗农。该假说将通过以下目标进行检验：目标1.评估Daam1在 肾小管发生的细胞连接的建立。Daam1介导肌动蛋白的假说 聚合调节钙粘附素介导的接触的形成，促进肾上皮化 将对小管进行测试。完成这一目标将提供对以前未被认识到的作用的洞察 Daam1在肾单位上皮化中的表达。目的2.明确Tuba在细胞连接形成过程中的作用 肾小球发育。拟议的实验将检验上皮性连接需要Tuba的假设。 在发育中的肾单位形成。完成这一目标将揭示图巴是否促进连接 上皮化肾单位的形成。总体而言，本申请中提出的实验将促进新的 肾上皮化和形态发生的细胞生物学机制 小管。

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that Daam1, a Wnt/ planar cell polarity effector, and Tuba (Dnmbp) are required for nephron morphogenesis, and unpublished data indicate that they are required for cell junction formation during epithelialization.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