Diversity Supplement: Novel Role of Nephron Epithelialization in Nuclear Signaling

多样性补充：肾单位上皮化在核信号传导中的新作用

• 批准号: 10853534
• 负责人: Rachel Katherine Miller
• 金额: $ 4.88万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10853534
• 关键词: Actins; Address; Adherens Junction; Adhesions; Area; Attenuated; Automobile Driving; Biological; Birth; Budgets; Cadherins; Cell Communication; Cell Nucleus; Cells; Childhood; Complex; Congenital Abnormality; Data; Defect; Development; Developmental Process; Embryo; End stage renal failure; Epithelium; Funding; Generations; Genetic; Goals; Grant; Human; Image; Intercellular Junctions; Kidney; Kidney Transplantation; Mediating; Microfilaments; Modeling; Morphogenesis; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrons; Nuclear; Pathologic; Pathway interactions; Polymers; 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; in vivo; insight; malformation; nephrogenesis; nephron progenitor; novel; parent grant; planar cell polarity; polymerization; stem cells

PROJECT SUMMARY/ ABSTRACT OF PARENT GRANT (2R01DK115655-04A1): NOVEL ROLE OF NEPHRON EPITHELIALIZATION IN NUCLEAR SIGNALING **R01 Project Summary/Abstract has been revised so that they are feasible, given that our grant budget was subjected to a global NIDDK reduction of 30% (the 5th year of the budget period was eliminated in addition to a 12% cut from each of years 1-4). 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.

父母赠款的项目摘要/摘要（2R01DK115655-04A1）： 核信号传导中的肾单位上皮化 ** R01项目摘要/摘要已修改，因此它们是可行的，因为我们的赠款预算是 在全球NIDDK减少30％（预算期限的第5年外，除了 从1 - 4年的每年削减12％）。 肾脏和尿路（cakut）的先天异常是小儿终止的最常见原因 - 肾脏疾病导致需要肾脏移植。它们发生在几乎2％的出生中，弥补 近四分之一的出生缺陷。但是，只有14％的病例具有已知的遗传原因。许多卡库特 病例是由肾单位形成的缺陷导致的，肾单位的形成是由所需的上皮小管组成的 为了适当的肾脏功能。先前的研究表明，平面细胞极性（PCP）的破坏 途径或外囊囊泡复合物导致肾小管畸形，表明这些 正确的小管形成需要组件。在我们先前的研究中，我们评估了微管发生 通过PCP和外循环络合物独立促进。我们研究了不同的模型 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的formin蛋白，并且 调节外囊囊泡靶向的DNMBP/TUBA，通过促进产生的生成来促进微管发生 肾单位祖细胞之间的细胞细胞接触。我们发现了一种利用WNT/PCP的新型机制 formin蛋白DAAM1驱动肾单位祖细胞之间的细胞连接形成，以生成小管 聚合肌动蛋白以稳定粘附蛋白在粘附连接处。此外，我们的结果表明胞外囊性 关联的组件DNMBP促进了连接组件的靶向启动这些细胞的形成 肾单位祖细胞之间的接触。尽管取得了这种进步，我们不了解细胞的形成 细胞接触影响小管上皮化和形态发生的发育过程 发展肾脏。为了解决这个重大问题，我们将以我们的重要发现为基础 评估细胞连接形成如何影响肾小管小管的发展：1）确定如何确定 DAAM1和DNMBP之间的相互作用调节肾单位祖细胞和 2）确定DAAM1在连接形成中的作用是否调节β-catenin的连接与Wnt 信号传递在肾脏发生过程中。总体而言，本应用程序中提出的实验将有助于新的 了解细胞如何相互作用和交流以进行多个相关性的微管发生 器官系统。对肾脏发育涉及的细胞生物学机制的定量评估是 新的研究领域将为上皮化和形态发生机制提供宝贵的见解 基础肾变生成过程。