The role of met receptor in morphogenesis and renewal of the intestinal epithelium

发育中和成人消化道中肠上皮的功能完整性依赖于对各种上皮细胞的增殖、存活、迁移、侵袭以及形态发生的严格控制。这些事件是由上皮细胞和周围间充质细胞产生的生长因子信号之间的协同相互作用决定的。肝细胞生长因子(HGF)是间充质细胞来源的多效性因子，具有促进和维持多种重要器官组织的作用。HGF通过特异性激活存在于上皮细胞表面的Met受体来实现其功能。Met/HGF受体轴调控的生物学过程包括上皮细胞的增殖、存活、迁移、侵袭以及形态发生。一些证据表明，Met/HGF受体轴可能在肠上皮的发育和更新中发挥关键作用。然而，由于HGF或Met受体缺陷小鼠的早期胚胎死亡，对HGF和Met/HGF受体在这些事件的调节中的具体作用知之甚少。我的研究计划的总体目标是确定HGF和Met受体在肠上皮形成和更新中的功能。为此，我们将利用不同的细胞和分子生物学方法应用于不同的上皮模型，以机械地定义Met受体下游的细胞内信号通路，这些信号通路与发育形态发生和肠上皮更新的基本生物学过程有关。

The functional integrity of the intestinal epithelium in the developing and adult digestive tract relies on a tight control of proliferation, survival, migration, invasion, as well as morphogenesis of various epithelial cell populations. These events are dictated by a concerted interplay between growth factors signals produced by epithelial and surrounding mesenchymal cells. The hepatocyte growth factor (HGF) is a pleiotropic factor of mesenchymal cell origin, which is well known to promote and maintain tissue organization of various vital organs. HGF accomplishes its functions through the specific activation of the Met receptor present at the cell surface of epithelial cells. Biological processes regulated by the Met/HGF receptor axis include epithelial cells proliferation, survival, migration, invasion, as well as morphogenesis. Several lines of evidence suggest that the Met/HGF receptor axis may play key functions in the development and renewal of the intestinal epithelium. However, because of the early embryonic death of HGF or Met receptor-deficient mice, little is known about the specific role of HGF and the Met/HGF receptor in the regulation of these events The overall objective of my research program is to define the function of HGF and the Met receptor in the formation and renewal of the intestinal epithelium. For this we will exploit various cellular and molecular biological approaches applied to various epithelial models to define mechanistically the intracellular signaling pathways downstream of the Met receptor that are implicated in biological processes fundamental to the developmental morphogenesis and the renewal of the intestinal epithelium.