Shp2-dependent and -independent signals in ureteric bud branching morphogenesis

输尿管芽分支形态发生中Shp2依赖性和非依赖性信号

• 批准号: 7197677
• 负责人: FRANK S DAVID
• 金额: $ 13.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197677
• 关键词: SDS polyacrylamide gel electrophoresis; biological signal transduction; enzyme activity; guanine nucleotide binding protein; immunoprecipitation; morphology; nephrogenesis; phosphorylation; polymerase chain reaction; protein isoforms; protein protein interaction; protein tyrosine phosphatase; ureter

DESCRIPTION (provided by applicant): During kidney development, ureteric bud (UB) cells undergo branching morphogenesis to form the distal collecting system. Aberrant branching may lead to developmental anomalies and regulate nephron number variation that contributes to hypertension and end-stage renal disease. A full understanding of the signals that regulate UB branching morphogenesis will therefore lead to the identification of regulators of these pathologic processes. The protein tyrosine phosphatase Shp2 is required to generate signals that drive branching morphogenesis, but its precise biochemical and developmental roles are unclear. In preliminary studies, I validated the importance of Shp2 in epithelial cell signaling, and also uncovered a novel, Shp2-independent pathway that may regulate additional aspects of UB development. I will use biochemical and cell biological approaches to define the components of these Shp2-dependent and -independent signaling pathways. I will also directly define the in vivo role of Shp2 in UB branching morphogenesis, and use ex vivo organ culture methods to further determine the roles of the signaling pathway components I identify in this developmental process. These studies will substantially advance our understanding of renal development and more fully define pathways that may apply to other pathologic conditions related to epithelial plasticity. The candidate for this K08 award, Frank David, is a pathologist who will receive advanced training in biochemistry and renal developmental biology through this work. His mentor, Benjamin Neel, is an expert in Shp2 and transgenic mouse studies. His consultants -- Joseph Bonventre, Lewis Cantley, Jordan Kreidberg, Andrew McMahon and Helmut Rennke -- are experts in phosphorylation-dependent signaling and renal pathophysiology and development, who will contribute substantially to his training during the course of this award. LAY SUMMARY: This work will define mechanisms in kidney development that may underlie several kidney-related birth defects and the development of high blood pressure. They will also advance our understanding of other pathologic processes, including metastasis and wound heaing, that share common signals and cellular behaviors with those defined here.

描述（由申请人提供）： 在肾脏发育过程中，输尿管芽（UB）细胞经历分支形态发生，形成远端集合系统。异常分支可能导致发育异常并调节肾单位数量变化，从而导致高血压和终末期肾病。因此，充分了解调节 UB 分支形态发生的信号将有助于识别这些病理过程的调节因子。 蛋白质酪氨酸磷酸酶 Shp2 是产生驱动分支形态发生的信号所必需的，但其精确的生化和发育作用尚不清楚。在初步研究中，我验证了 Shp2 在上皮细胞信号传导中的重要性，并且还发现了一种新的、不依赖于 Shp2 的途径，该途径可能调节 UB 发育的其他方面。我将使用生化和细胞生物学方法来定义这些依赖于 Shp2 和 -独立的信号通路。我还将直接定义Shp2在UB分支形态发生中的体内作用，并使用离体器官培养方法进一步确定我确定的信号通路成分在此发育过程中的作用。这些研究将极大地增进我们对肾脏发育的理解，并更全面地定义可能适用于与上皮可塑性相关的其他病理状况的途径。 K08 奖的候选人 Frank David 是一位病理学家，他将通过这项工作接受生物化学和肾脏发育生物学方面的高级培训。他的导师 Benjamin Neel 是 Shp2 和转基因小鼠研究方面的专家。他的顾问——Joseph Bonventre、Lewis Cantley、Jordan Kreidberg、Andrew McMahon 和 Helmut Rennke——都是磷酸化依赖性信号传导和肾脏病理生理学和发育方面的专家，他们将在获奖期间为他的培训做出重大贡献。 摘要：这项工作将定义肾脏发育的机制，这些机制可能是多种与肾脏相关的出生缺陷和高血压发展的基础。它们还将促进我们对其他病理过程的理解，包括转移和伤口愈合，这些过程与此处定义的信号和细胞行为具有共同的信号和细胞行为。