细胞滋养细胞（CTB）的祖细胞特性是维系胎盘结构与功能动态变化以适应胎儿发育所需的关键因素之一。本研究基于前期数据和前人成果，创新性的提出“缺氧环境经HIF1α/Notch3/Myc信号通路，影响滋养细胞自我更新与分化的动态平衡，引起滋养细胞合体化不足和胎盘发育异常”可能是子痫前期（PE）发生的重要机制之一。项目拟利用CTB细胞分化相关转录组的生物信息学分析结果、体外原代和永生细胞模型和横断面研究，阐明：1）Notch3/Myc信号通路介导的CTB细胞周期调控和干性维持；2）缺氧暴露经HIF1α增强Notch3信号强度，破坏滋养细胞干性维持与分化平衡，导致合体化异常；3）HIF1α/Notch3/Myc通路介导的细胞周期阻滞异常损害滋养细胞干性特征与PE发生相关。本研究将为进一步阐明人胎盘滋养细胞干性维持与分化调控的分子机制提供理论支撑，为PE的早期诊断及靶向治疗提供新思路。

The progenitor cytotrophoblast cells (CTB) is a significant contributor to dynamic changes of the placental structure and function which are required to accommodate the growth of fetus. Based on our preliminary data and published results by other authors, here we have proposed a new hypothesis that hypoxia environment can affect the dynamic balance between CTB self-renewal and differentiation via HIF1α/Notch3/Myc signal pathway, lead to the deficiency of trophoblast fusion as well as the abnormal development of placenta, which might be one of important underlying leading causes of the preeclampsia (PE). In this project, we intend to use our bioinformatics analysis results obtained from dozens of transcriptome data defining CTB differentiation from multiple sources, in vitro primary and eternal cells model and cross-sectional study to clarify the following three concerns: 1) The role of Notch3/Myc signal pathway in the cell cycle regulation and the stem cell maintenance of cytotrophoblast. 2) Hypoxia exposure enhances the Notch3 signal intensity via HIF1α, disrupting the balance between the stem cell maintenance and CTB differentiation, and leading to the abnormality of trophoblastic cell fusion. 3) HIF1α/Notch3/Myc pathway mediates dysregulation of cell cycle restriction and damage of stem cell properties, which might be correlated with the occurrence of PE. This study will provide a creative theoretical support for a new molecular mechanism in the maintenance and differentiation of human placental trophoblast progenitor CTB cell, leading to a new wayfor the early diagnosis and targeted therapy of PE.