Regulation of Cell Signaling and Branching morphogenesis

细胞信号传导和分支形态发生的调节

• 批准号: 405644-2012
• 负责人: Bridgewater, Darren
• 金额: $ 2.19万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629479
• 关键词: Regulation; Cell; Signaling; Branching; morphogenesis

Branching morphogenesis, defined as the growth and branching of epithelial tubes, is fundamental to the formation of the vascular system, nervous system, kidney, lung, pancreas, mammary and salivary glands. During branching morphogenesis groups of epithelial cells form branches that have defined branch patterns, length, diameter, shape and spacing and undergo numerous cellular activities. How cells regulate multiple cellular events through a single receptor is not well understood. The activation of the Ret receptor tyrosine kinase by its ligand Glial cell-line derived neurotrophic factor (Gdnf) leads to multiple cellular events in the kidney and represents and attractive model to answer this question. How Gdnf/Ret signaling is regulated and how it alters the behavior of epithelial cells to undergo the many distinct cellular processes is not clear. It is suspected activation of distinct signaling pathways may determine the biological output. We and others have shown that ß-catenin is essential for branching morphogenesis in numerous organ systems. In the cell ß-catenin is involved in cell adhesion by binding to adherens junctions or is in a cytoplasmic/nuclear component that acts to transduce Wnt signals. Recent studies have demonstrated a novel Ret kinase/ß-catenin signaling pathway in multiple endocrine neoplasia's and data from my lab strongly supports an essential role for this novel pathway. To address this possibility I propose, to (1) examine if ß-catenin acts upstream of Ret signaling by determining if it has a direct effect on Gdnf expression (and other genes known to regulate Gdnf expression) and (2) to ask whether ß-catenin is activated in response to Gdnf/Ret signaling and regulates distinct genes and biological functions. These findings could be applied to all developing, mature, and diseased organ systems as the signaling pathway and genes identified here are likely fundamental processes. Further Gdnf/Ret signaling is essential for the development and maintenance of the urogential and nervous systems. Identifying a novel Ret/ß-catenin signaling pathway could provide novel molecular approaches for repair in the nervous, kidney and reproductive systems.

分支形态发生，定义为上皮管的生长和分支，是血管系统、神经系统、肾、肺、胰腺、乳腺和唾液腺形成的基础。在分支形态发生期间，上皮细胞群形成具有限定的分支模式、长度、直径、形状和间距的分支，并经历许多细胞活动。细胞如何通过单一受体调节多个细胞事件尚不清楚。Ret受体酪氨酸激酶被其配体胶质细胞系衍生的神经营养因子（Glial cell-line derived neurotrophic factor，GDNF）激活导致肾脏中的多个细胞事件，并且代表了回答这个问题的有吸引力的模型。Gdnf/Ret信号是如何调节的，以及它如何改变上皮细胞的行为以经历许多不同的细胞过程尚不清楚。据推测，不同信号通路的激活可能决定生物输出。我们和其他人已经证明β-连环蛋白对于许多器官系统的分支形态发生至关重要。在细胞中，β-连环蛋白通过与粘附连接结合而参与细胞粘附，或者在细胞质/核组分中起作用以抑制Wnt信号。最近的研究已经证明了一种新的Ret激酶/β-连环蛋白信号通路在多发性内分泌肿瘤中的作用，并且来自我实验室的数据强烈支持这种新通路的重要作用。为了解决这种可能性，我建议（1）通过确定β-连环蛋白是否对GDNF表达（以及已知调节GDNF表达的其他基因）具有直接影响来检查β-连环蛋白是否在Ret信号传导的上游起作用，以及（2）询问β-连环蛋白是否响应于GDNF/Ret信号传导而被激活并调节不同的基因和生物学功能。这些发现可以应用于所有发育，成熟和患病的器官系统，因为这里确定的信号通路和基因可能是基本过程。进一步的GDNF/Ret信号传导对于泌尿生殖系统和神经系统的发育和维持是必不可少的。鉴定一种新的Ret/β-连环蛋白信号通路可以为神经、肾脏和生殖系统的修复提供新的分子方法。