滋养细胞SGK1介导早孕母胎界面血管重塑及稳态维持的机制研究

Trophoblastic proliferation and differentiation in an orderly manner play a critical role in the placentation and maintencance of early pregnancy. The pathological mechanism underlying early pregnancy loss (EPL) is greatly related with poorly trophoblastic differentiation. Our previous study on EPL chorionic tissues found that SGK1 was downregulated significantly in trophoblastic cells of EPL when compared with the controls, which suggestting that SGK1 has an important role in early placental development and maintenance of pregnancy. In this protocol, we aim to reveal the characteristics of spatial-temporal expression, regulative pattern and related molecular mechanisms during the development of trophoblastic cells, vascular remodeling and early pregnancy by using cellular co-colture system as a proliferation-differentiation model , combination with the in vitro gene control techniques and stress-induced mouse model. Ultimately, we aim to determinate the mechanism of vascular remodeling, pathologic mechanism of EPL, and provide valuable information and seek possible direction for cellular and molecular treatment.

有序的滋养细胞增殖、分化进程在胎盘母胎界面血管重塑及妊娠维持中起着重要的作用。早期妊娠丢失(EPL)等病理性妊娠与早期妊娠滋养细胞分化不良有关。我们前期研究发现，与细胞增殖和分化相关的信号节点蛋白- - SGK1蛋白激酶在早期妊娠绒毛组织中有表达，且表达水平与妊娠结局密切相关。提示，SGK1在早期胎盘发育中扮演重要角色。本项目拟采取早期妊娠不同时期滋养细胞构建滋养细胞在体发育进程，并结合体外基因表达调控技术、动物模型及小动物PET呈像技术，完整地揭示SGK1在滋养细胞增殖-分化进程中表达的时空特征、表达调控模式及相关重要分子间作用方式，并应用小鼠流产模型观察SGK1在病理性妊娠持中的作用及机制，为揭示早期妊娠滋养细胞、胎盘血管网络构建以及最终寻求早期妊娠丢失可能分子治疗方法提供有价值的理论依据。

早期妊娠丢失(EPL)等病理性妊娠与早期妊娠滋养细胞分化不良有关。本项目采取早期妊娠滋养细胞系体外雌孕激素作用模拟早期妊娠滋养细胞微环境，并结合基因表达调控技术、动物模型等技术，完整地揭示SGK1在滋养细胞增殖-分化进程中表达的时空特征、表达调控模式及相关重要分子间作用方式，并应用小鼠流产模型观察SGK1在病理性妊娠持中的作用及机制，结果发现：1. 滋养细胞的功能如增殖、迁移和侵入等受到雌孕激素的调控，且与妊娠结局明显相关；2. SGK1 介导了雌孕激素对滋养细胞功能如增殖、迁移、侵袭及血管生成等功能的调控；3. 滋养细胞系HTR8/SVneo细胞中SGK1表达水平敲低后，滋养细胞功能如增殖、迁移、侵袭及血管生成功能受显著影响，相关分子机制显著降低，从而可能影响妊娠结局。结论：SGK1介导了雌、孕激素对早期妊娠中滋养细胞增殖、迁移、侵袭及血管生成的调控，对妊娠的维持具有重要作用。