SMEK1通过调控Tiam1抑制滋养细胞侵袭参与胎儿生长受限发病的研究

FGR作为最常见的妊娠期并发症，其发病率逐年上升。由于发病机制尚不明确，FGR缺乏有效的预防、治疗手段。我们前期的研究已经发现蛋白磷酸酶2A家族的基因Smek1敲除小鼠在胎儿期出现FGR的症状。SMEK1表达于人早孕蜕膜iEVT、绒毛及胎盘CTB，且在FGR患者胎盘中表达下降。体外实验证实SMEK1缺失损害EVT迁移侵袭能力，且通过RNA-Seq及生物信息学分析得到了靶基因Tiam1。由此我们提出假说：SMEK1通过影响EVT侵袭力在FGR发生中发挥重要作用。为此，课题组拟以FGR患者胎盘组织和Smek1敲除小鼠为研究对象，首先明确SMEK1在胎盘中的分布及表达情况，通过体外细胞实验对靶基因Tiam1进行验证并明确其下游信号通路；同时构建Smek1胎盘特异性敲除小鼠，体内探究SMEK1对EVT参与的胎盘发育的影响，为阐明SMEK1在FGR发病中的作用提供实验依据。

As the most common pregnancy complication, morbidity for FGR is gradually increasing. No approved treatment is available for pregnant women affected with FGR，because the pathogenesis is not clear. In previous study, we identified that lack of the protein phosphatase 2A family gene Smek1 during mouse pregnancy drives FGR. SMEK1 is expressed in iEVT of the first trimester decidua and CTB in villous and placenta. In addition, the expression of SMEK1 in the placenta of FGR pregnant women decreases. In vitro experiments, we confirmed that deletion of SMEK1 impaired the migration and invasion of EVT.The target gene Tiam1 was obtained by RNA-seq and bioinformatics analysis. Based on above results, we hypothesize that SMEK1 plays a critical role in the occurrence of FGR via affecting invasion of EVT. Patients with FGR and model mice are the main study object.In this proposed project, we aim to describes the distribution and expression of SMEK1 in placenta, and then verified the target genes predicted by RNA-Seq through in vitro cell study, to clarify its downstream signaling pathway; At the same time, construct Smek1 placenta-specific knockout mice to explore the effect of Smek1 on EVT involved in the development of placenta in vivo, and provide experimental evidence for elucidating the role of SMEK1 in the pathogenesis of FGR.