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

• 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
• 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

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.

项目摘要/摘要： 肾单位上皮化在核信号中的新作用 肾脏和尿路的先天异常（Cakut）是小儿终末期肾脏疾病的最常见原因，导致需要进行肾脏移植。它们发生在几乎2％的出生中，几乎构成了所有出生缺陷的四分之一。但是，只有14％的病例具有已知的遗传原因。许多Cakut病例是由于肾形成的缺陷而导致的，肾脏的形成是由肾脏正常功能所需的上皮管组成的。先前的研究表明，平面细胞极性（PCP）途径或外囊域复合物的破坏会导致肾小管畸形，表明这些成分是正确的管形成所必需的。在我们先前的研究中，我们评估了如何通过PCP和外囊酶独立地支持结核病。我们研究了一种不同的模型，DAAM1（一种将肌动蛋白丝作为Wnt/Planar细胞极性途径的一部分组装而成的formin蛋白，而调节外生粒细胞靶向的DNMBP/TUBA，通过促进Nephron odemenitor细胞之间的细胞细胞接触来促进Tuberonesis。我们发现了一种新型机制，该机制利用Wnt/PCP formin蛋白DAAM1驱动肾单位祖细胞之间的细胞连接形成，以通过聚合肌动蛋白聚合稳定粘附蛋白在粘附连接处产生TUBEROS。此外，我们的结果表明，与外囊肿相关的成分DNMBP支持连接成分的靶向，以启动肾单位祖细胞之间这些细胞接触的形成。尽管取得了这种进步，但我们不理解细胞接触的形成如何影响肾脏发育中的小节上皮化和形态发生的发育过程。为了解决这个重大问题，我们将以我们的重要发现为基础，以评估细胞连接形成如何影响肾管的发展：1）确定DAAM1和DNMBP之间的相互作用如何调节肾单位祖细胞祖细胞和2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确定在连接构造中的作用，以调节beta-caterin ne ne nent nent nent nent nent wheint w. nnt w. restrus。总体而言，本应用程序中提出的实验将有助于对细胞相互作用和通信以进行与多器官系统相关的结核病的新了解。对肾脏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，它将为造成结核过程的上皮化和形态发生机制提供宝贵的见解。