DKK3表达缺陷导致滋养细胞分化异常在子痫前期发病中的作用机制

Preeclampsia (PE) is one of the main causes of maternal mortality, and its pathogenesis remains elusive. One possible mechanism of PE is the trophoblast (TB) differentiation defects. Our previous study found that the deficiency of DKK3 expression results in vascular smooth muscle cell differentiation and angiogenesis failure. It is reported that DKK3 expression is identical to the primary trophectoderm in TB differentiation model genome, suggesting it is involved in embryo implantation and placentation. Our preliminary experiments showed that the expression of DKK3 was significantly increased in the early stage of TB differentiation; knockdown of DKK3 gene significantly inhibited the expression of TB differentiation markers (such as CDX2, KRT7); Wnt/β-catenin pathway was involved in DKK3 induced TB differentiation; Mid gestation serum DKK3 secretion level among PE patients was lower than heathy women. Therefore, we hypothesize that DKK3 may be capable of regulating TB differentiation, and its expression defects may trigger abnormal TB differentiation, which eventually leads to PE. In this proposed project, the role and molecular mechanism of DKK3/Wnt signaling pathway on PE will be examined through molecular biological techniques, immunohistochemistry, ELISA，etc., so as to provide some insight on new clinical treatment targets of PE.

子痫前期（PE）是孕产妇死亡的主要原因之一，其发病机制尚未明确。滋养细胞（TB）分化缺陷是PE发生的可能机制之一。我们前期研究已揭示：DKK3缺陷可致血管平滑肌细胞分化失败,影响血管功能。文献报道DKK3在TB分化模型的转录基因组表达与原代滋养外胚层相同，可能参与胚胎植入、胎盘发生发育。预实验结果提示：TB分化早期DKK3表达增加；敲低DKK3基因显著抑制TB分化标志物（如CDX2、KRT7）表达；Wnt/β-catenin信号通路参与DKK3诱导的TB分化；PE患者孕中期血清DKK3蛋白分泌较未发病孕妇减少。因此，我们推测：DKK3可能调控TB分化，其表达缺陷可引起TB分化异常，从而导致PE发生。本项目将通过细胞实验、动物实验和病例对照研究三方面，采用分子生物学技术、免疫组化、ELISA等方法，探讨DKK3/Wnt信号通路对PE的作用及分子机制，从而为临床治疗PE靶点研究提供新思路。