Genetic Control of Ureter and Kidney Development

输尿管和肾脏发育的遗传控制

基本信息

批准号：
8035312
负责人：
FRANKLIN D COSTANTINI
金额：
$ 43.29万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-20 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035312
关键词：
Address Affect Behavior Biological Models Cell surface Cells Characteristics Chemicals Chimera organism Complex Congenital Abnormality Cyst Cystic kidney Data Defect Development Duct (organ) structure Epithelium Equilibrium Event FGF10 gene FGF7 gene Feedback Fibroblast Growth Factor Fibroblast Growth Factor Receptor 2 GDNF gene Gene Expression Gene Proteins Genetic Genetic Crosses Growth Growth Factor Hepatocyte Growth Factor Human Hypertension Image Kidney Knock-out Lateral Lead MAP Kinase Gene Mediating Mesenchyme Metanephric Diverticulum Methods Mitogen-Activated Protein Kinases Modeling Morphogenesis Mus Mutation Nature Organ Organ Culture Techniques Pathway interactions Pattern Phenotype Play Positioning Attribute Process Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Relative (related person)Renal function Role Signal Pathway Signal Transduction Staging Stimulus Structure of mesonephric duct System Testing Time Ureter Urinary tract base cell type embryonic stem cell in vivo inhibitor/antagonist lung development malformation meetings mouse model mutant nephrogenesis prevent receptor repaired research study response ureter dilatation urinary urinary tract obstruction

项目摘要

DESCRIPTION (provided by applicant): Congenital abnormalities of the kidney and urinary tract (CAKUT) are among the most common birth defects in humans. Many of them result from alterations in the normal processes of ureteric bud induction, growth, and branching during the development of the ureter and the renal collecting duct system. These events are controlled, in part, by signaling networks that include secreted growth factors, cell-surface tyrosine kinase receptors, multiple intracellular signaling pathways, and negative feedback mechanisms that keep the signaling networks in balance. GDNF is a mesenchymally-derived growth factor that signals to the ureteric bud epithelium via the Ret receptor tyrosine kinase and the co-receptor Gfr11. In mouse models, GDNF signaling plays a major role in ureter and kidney development, and in humans, RET and GDNF mutations are associated with renal agenesis. Ret activates several intracellular mechanisms, including the Erk MAP kinase pathway, and the response to Ret is controlled through feedback regulation by the intracellular protein Sprouty1. While Sprouty1 is thought to act primary on the Erk MAP kinase pathway, its mechanism is not well understood. However, it is clear that the negative feedback provided by Sprouty1 is critical, as its absence leads to multiple and ectopic ureters, hydroureter, multiplex kidneys with abnormal branching of collecting ducts, and renal cysts. This proposal focuses on the tyrosine kinase signaling networks that control the normal outgrowth of the ureteric bud to form a single and correctly positioned ureter, and then regulate its complex patterns of growth and branching during kidney development. Using the mouse as a model system, we employ a variety of genetic approaches to investigate three related issues. First, we examine the mechanism by which Sprouty1 prevents ureteric bud cells from over-responding to GDNF and other growth factors such as FGFs, and how its absence leads to malformations and cysts in the ureteric bud-derived epithelium. Next, we investigate the unexpected finding that ureters and kidneys can sometimes develop to an advanced stage in mice completely lacking GDNF or Ret, when the negative regulation provided by Sprouty1 is also removed. This suggests that a balance between positive stimuli and negative feedback is perhaps more important than the specific effects of any one growth factor. It also implies that other growth factors that signal through different tyrosine kinase receptors must overlap, to a large degree, with GDNF in its ability to promote and pattern growth and branching of the ureter and collecting ducts. We therefore investigate the roles of several candidates, including fibroblast growth factors (FGFs) and hepatocyte growth factor (HGF), in these processes. This proposal will advance the field by providing a deeper understanding of the multilayered control mechanisms that mediate development of a normal ureter and kidney, and may suggest new ways to prevent or treat CAKUT. Among the most common types of birth defects are those affecting the kidneys and urinary tract. These include abnormalities causing urinary tract obstruction, as well as those that reduce the size and function of the kidney and can lead to hypertension. By identifying the genes and proteins that control the growth of the ureter and kidney from a small group of cells to a complex organ, it may eventually be possible to prevent or repair such birth defects.

描述（由申请人提供）：肾脏和尿路（Cakut）的先天性异常是人类最常见的先天缺陷之一。其中许多是由于输尿管发育过程中输尿管芽诱导，生长和分支的正常过程的改变而导致的，并且肾脏收集管系统的发展。这些事件部分通过包括分泌生长因子，细胞表面酪氨酸激酶受体，多个细胞内信号通路以及负面反馈机制的信号网络来控制这些事件，以使信号网络保持平衡。 GDNF是一种间质衍生的生长因子，通过RET受体酪氨酸激酶和共受体GFR11向输尿管芽上皮信号。在小鼠模型中，GDNF信号在输尿管和肾脏发育中起着重要作用，在人类中，RET和GDNF突变与肾脏发育不全有关。 RET激活了包括ERK MAP激酶途径在内的几种细胞内机制，并且对RET的反应通过细胞内蛋白Sprouty1的反馈调节来控制。虽然Sprouty1被认为是在ERK MAP激酶途径上起作用的，但其机制尚不清楚。但是，很明显，Sprouty1提供的负反馈至关重要，因为它的缺失会导致多个和异位输尿管，水力流核，多重肾脏，具有收集管道异常分支的多重肾脏以及肾囊肿。该建议着重于控制输尿管芽的正常生长以形成单个且正确定位的输尿管，然后调节其在肾脏发育过程中的复杂生长和分支模式。使用小鼠作为模型系统，我们采用多种遗传方法来研究三个相关问题。首先，我们研究了发芽1的机制，可以防止输尿管芽细胞过度响应到GDNF和其他生长因子（例如FGF），以及其缺失如何导致输尿管芽源性上皮的畸形和囊肿。接下来，我们调查了一个意外的发现，即输尿管和肾脏有时会发展为完全缺乏GDNF或RET的小鼠的高级阶段，而Sprouty1提供的负调节也被删除。这表明，正面刺激和负反馈之间的平衡可能比任何一种生长因子的特定效应都重要。这也意味着，通过不同酪氨酸激酶受体发出信号的其他生长因子必须在很大程度上重叠，GDNF具有促进输尿管和收集管道的促进和模式生长和分支的能力。因此，我们研究了几个候选者的作用，包括成纤维细胞生长因子（FGF）和肝细胞生长因子（HGF）在这些过程中。该建议将通过对介导正常输尿管和肾脏发展的多层控制机制有更深入的了解，并可能提出预防或治疗Cakut的新方法，从而提高该领域。最常见的先天缺陷类型是影响肾脏和尿路的类型。这些包括引起尿路阻塞的异常，以及降低肾脏大小和功能并可能导致高血压的异常。通过识别控制输尿管和肾脏从一小组细胞到复杂器官的生长的基因和蛋白质，最终可能有可能预防或修复此类先天缺陷。