滋养层细胞增殖和分化是形成功能性胎盘、决定妊娠成功与否的关键过程。已有体外研究证明，磷酸酶Sh2的突变导致滋养层干细胞凋亡。我们的预实验发现，Shp2在胎盘发育不同阶段滋养层细胞中的缺失会导致滋养层干细胞的减少、滋养层前体细胞的增殖及分化障碍和滋养层细胞侵袭能力的减弱。据此，我们推测Sh2在胎盘发育的不同阶段和不同滋养层细胞类型中都起重要作用，提出关键科学问题“Shp2信号如何调控胎盘滋养层细胞的增殖和分化从而维持胎盘的正常功能”。本项目中，我们拟利用多种转基因小鼠模型、人胎盘样本和体外滋养层细胞系模型，系统研究：（1）Shp2介导的信号通路对胎盘滋养层细胞增殖和分化过程的调控机制；（2）Shp2信号异常相关的滋养层细胞缺陷导致先兆子痫的发病机理。通过本项目，我们将进一步解析胎盘滋养层细胞增殖和分化的调控机理，为胎盘相关妊娠疾病的诊断和治疗提供新的理论依据。

Trophoblast proliferation and differentiation are critical processes for forming functional placenta and successful pregnancy. It has been shown that phosphatase Shp2 mutation resulted in apoptosis of trophoblast stem cells in vitro. Our preliminary experiments found that Shp2 deletion in trophoblast cells at certain stages of placental development led to reduced trophoblast stem cells, defective proliferation and differentiation of trophoblast progenitor cells, and decreased trophoblast invasion. Based on these data, we suspect that Shp2 plays an important role at different stages of placental development and in different trophoblast cell types, and propose the key scientific question as “how Shp2 signaling regulate trophoblast proliferation and differentiation to maintain normal placental functions”. In the present project, employing multiple placenta-specific mouse models, human placental samples as well as cultured trophoblast cell lines, we will investigate: (1) the mechanism of Shp2-mediated signaling pathway during the proliferation and differentiation of placental trophoblast cells；and (1) the pathogenesis of preeclampsia caused by defective trophoblast due to abnormal Shp2 signaling. Our project is to clarify further the molecular mechanism of the proliferation and differentiation of placental trophoblast cells, providing new theoretical basis for the diagnosis and treatment of placenta-related diseases.