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：
7565853
负责人：
FRANKLIN D COSTANTINI
金额：
$ 43.56万
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/7565853
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）：先天性肾脏和尿路异常 (CAKUT) 是人类最常见的出生缺陷之一。其中许多是由于输尿管和肾集合管系统发育过程中输尿管芽诱导、生长和分支的正常过程发生改变所致。这些事件部分地受到信号网络的控制，包括分泌的生长因子、细胞表面酪氨酸激酶受体、多种细胞内信号通路以及保持信号网络平衡的负反馈机制。 GDNF 是一种间充质来源的生长因子，通过 Ret 受体酪氨酸激酶和辅助受体 Gfr11 向输尿管芽上皮发出信号。在小鼠模型中，GDNF 信号传导在输尿管和肾脏发育中发挥重要作用，而在人类中，RET 和 GDNF 突变与肾发育不全相关。 Ret 激活多种细胞内机制，包括 Erk MAP 激酶通路，并且对 Ret 的反应通过细胞内蛋白 Sprouty1 的反馈调节进行控制。虽然 Sprouty1 被认为主要作用于 Erk MAP 激酶通路，但其机制尚不清楚。然而，很明显，Sprouty1 提供的负反馈至关重要，因为它的缺失会导致多发和异位输尿管、输尿管积水、集合管异常分支的多发肾和肾囊肿。该提案重点关注酪氨酸激酶信号网络，该网络控制输尿管芽的正常生长，形成单个且位置正确的输尿管，然后在肾脏发育过程中调节其复杂的生长和分支模式。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 Sprouty1 防止输尿管芽细胞对 GDNF 和其他生长因子（如 FGF）过度反应的机制，以及它的缺失如何导致输尿管芽衍生上皮的畸形和囊肿。接下来，我们研究了一个意外的发现，即当 Sprouty1 提供的负调节也被消除时，完全缺乏 GDNF 或 Ret 的小鼠的输尿管和肾脏有时会发育到晚期。这表明积极刺激和消极反馈之间的平衡可能比任何一种生长因子的具体作用更重要。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与 GDNF 重叠，因为 GDNF 能够促进和模式化输尿管和集合管的生长和分支。因此，我们研究了几种候选因子，包括成纤维细胞生长因子（FGF）和肝细胞生长因子（HGF）在这些过程中的作用。该提案将通过提供对介导正常输尿管和肾脏发育的多层控制机制的更深入理解来推进该领域的发展，并可能提出预防或治疗 CAKUT 的新方法。最常见的出生缺陷类型是影响肾脏和泌尿道的缺陷。其中包括导致尿路梗阻的异常，以及导致肾脏大小和功能减小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群细胞发育成复杂器官的基因和蛋白质，最终可能可以预防或修复此类出生缺陷。