母-胎界面免疫微环境恶化导致子痫发生的信息转导机制

Immune homeostasis is one of the key factors leading to eclampsia, but its mechanism remains unknown. Our previous studies have established a murine model of eclampsia using Toll-like receptor (TLR) ligand and found that there are significant differences in the proportion and phenotype of uterine immune cell subsets between preeclampsia mice and normal pregnancy mice. It suggests that the disorders in the feto-maternal microenvironment may be related with the occurrence and development of eclampsia. In this proposal, mouse preeclampsia models and clinical samples will be used to elucidate the signaling mechanism in eclampsia using techniques including multicolor flow cytometry and magnetic-affinity cell sorting. Dynamic observation will be performed on alteration of immune cell phenotype and function in feto-maternal microenvironment in preeclampsia subjects. Cell signaling network will be gradually drawn out to clarify how immune cells migrate and what is the relationship among immune cell subsets, inflammatory factors, and TLR signaling. Expected data will be beneficial to provide a new theoretical basis for understanding the pathogenesis and more effective prevention and treatment on preeclampsia.

免疫稳态失衡是导致子痫发生的关键因素之一，其作用机制不明。我们前期研究已成功利用 Toll样受体(TLR)的配体诱发并建立子痫小鼠模型。与正常妊娠相比，子痫前期小鼠母-胎界面免疫细胞亚群构成和表型均存在显著差异。这提示母-胎界面免疫微环境紊乱对子痫的发生及发展可能具有关键作用。本课题拟利用子痫前期小鼠模型和临床组织样本，借助于多色流式细胞术和磁珠亲和细胞分选术等技术进行系统性研究，动态观察子痫前期及正常妊娠时母-胎界面微环境中免疫活性细胞表型、功能变化规律和细胞迁移规律，阐明免疫细胞亚群、炎症因子及TLR信号间的内在联系，逐步揭示子痫发病过程中的信息转导机制，为提高子痫预防和诊治针对性提供理论依据。

免疫稳态失衡是导致子痫前期发生的关键因素之一，其作用机制不明。我们研究中已成功利用TLR9的激动剂CPG-ODN诱发并建立子痫前期小鼠模型。与正常妊娠相比，子痫前期小鼠母胎界面免疫功能失衡，炎症因子mRNA以及蛋白表达水平升高，血管内皮生长因子表达水平下降，这提示TLR9在子痫前期的发生及发展中可能具有关键作用。本课题利用子痫前期模型小鼠和临床组织样本，动态观察子痫前期以及正常妊娠时母-胎界面微环境TLR9的表达变化.利用基础实验以及表达谱芯片分析研究炎症因子、血管内皮生长因子与TLR9信号间的联系，指出部分敲除TLR9，使细胞侵袭和迁移能力增强，进而减少子痫前期的发病。同时我们发现了可以早期诊断子痫前期的外周血标志物hsa_circ_0036877。这些都为提高子痫前期的预防和诊治提供了更有效的理论依据。