子痫前期（PE）是导致母儿死亡的重要原因。早期绒毛外滋养细胞(EVT)分化障碍可能是根本起因，但该调控机制尚未阐明。本课题组1）前期实验，发现PE胎盘组织FOXD3高表达，利用新建的人胚胎干细胞（hESC）滋养层分化模型及CRISPR/Cas9技术敲除FOXD3提示促进EVT分化且RND3表达上调；2）既往研究，已揭示RND3调控HIF1α通路的分子机制，而后者是已知的调控EVT分化的重要因子。同时，本课题组已获赠近期首次分离的人滋养干细胞株（hTSC）。以此为基础，本项目拟结合新型的hESC/hTSC模型以及前期构建的小鼠动物模型，探讨FOXD3结合抑制RND3表达，降低HIF1α蛋白稳定而导致EVT分化障碍引起PE的调控途径和分子机制。并在已构建的PE特异性诱导多能干细胞模型中针对FOXD3基因尝试表型修复。期望为PE引入新的研究模型并提供理论依据，也为进一步临床防治提供新思路。

Preeclampsia (PE) is the main predisposing factor leading to maternal and fetal death in pregnancy. Dysfunction of early extravillous cytotrophoblast (EVT) differentiation may be the underlying cause, but its regulatory network has not been fully elucidated. 1) In our preliminary study, we found that FOXD3 is highly expressed in PE placenta. By using newly established hESC-trophoblast differentiation model and CRISPR/Cas9 technology we revealed knockout of FOXD3 promotes EVT differentiation with up-regulated RND3 expression. 2) In our previous studies, we have illustrated the molecular mechanism how RND3 modulated the HIFlαpathway, which is also known as an EVT differentiation regulator. Meanwhile, we have been authorized to use the first isolated human hTSCs. Based on above, here we plan to combine the new hESC/hTSC models with the previous animal model to explore the regulatory pathway and molecular mechanism in EVT differentiation disorder, where FOXD3 bind and inhibit RND3 to reduce HIF1α protein stability. Also, we attempt to repair the abnormal FOXD3 gene for restoring the EVT phenotype in a constructed PE-specific induced pluripotent stem (iPS) model. It is believed that our study will evidence new research models, and provide new insights for further study, clinical PE prevention and treatment.