Crosstalk between cAMP and ERK signalling pathways in tubulogenesis

小管发生是上皮器官发育的基础。在三维(3D)厚的胶原凝胶中生长的Madin-Darby犬肾(MDCK)细胞是一个有用的简化模型，可以用来研究肾小管的形成。在该系统中，肝细胞生长因子(HGF)可诱导细胞发生小管。参与调节小管形成的下游信号通路正在深入研究中。已经证明，ERK的长时间激活是这一过程中的一个关键事件。因此，识别在小管形成过程中调节ERK活性的信号通路具有重要的意义。令人惊讶的是，人们对重要的第二信使环磷酸腺苷(CAMP)在小管形成中的作用知之甚少。在本项目中，将研究cAMP在调节小管发生中的作用及其与ERK信号的串扰。三个主要问题将被解决：(I)cAMP在小管形成中起什么作用；(Ii)cAMP依赖的信号和ERK通路之间是否存在串扰；(Iii)cAMP信号的区划起到什么作用。

Tubulogenesis is fundamental to the development of epithelial organs. Madin-Darby canine kidney (MDCK) cells growing in 3 dimensional (3D) thick collagen gels represent a useful simplified model, where tubulogenesis can be studied. In this system, tubulogenesis could be induced by treatment of the cells with Hepatocyte Growth Factor (HGF). Downstream signaling pathways involved in the regulation of tubulogenesis are under intensive investigation. It has been demonstrated that prolonged ERK activation is a key event in this process. Therefore, identification of signaling pathways resulting in modulation of ERK activity during tubulogenesis is of fundamental significance. Surprisingly little is known about the role of the important second messenger cyclic AMP (cAMP) during tubulogenesis. In the present project the role of cAMP in regulation of tubulogenesis and its crosstalk with ERK signaling will be studied. Three major questions will be addressed: (i) what role does cAMP play in tubulogenesis; (ii) is there a crosstalk between cAMP-dependent signaling and ERK pathway; (iii) which role does the compartmentalization of cAMP signaling play.