妊娠过程中类固醇激素合成和代谢紊乱导致子痫前期的发生发展的机制

Preeclampsia has been one of the most severe Obstetric syndromes that bring big burdens for the fetal and maternal health. Based on the evidence that the placenta is the principal endocrine organ during pregnancy, the present project is aiming to address the critical scientific question as to how the occurrence and development of preeclampsia is affected by the abnormalities in steroid hormones during pregnancy. We are going to systematically analyze the abnormalities in the synthesis and metabolism of steroid hormones along the pregnant process in preeclamptic patients, and to explore the underlying mechanisms from the aspects of immune regulation and epigenetic regulation. We will further investigate the regulation of multiple cell interactions at the feto-maternal interface and the adaptation of maternal organs by placenta-derived steroid hormones, in order to clarify the pathological machinery of the adverse pregnant outcomes that are derived from the abnormal steroid hormone synthesis. The present study will reveal the molecular relationship between the imbalanced steroid hormones synthesis and the occurrence of preeclampsia, and will provide new insight into the diagnosis and intervention of the disease.

本项目针对临床上对母婴健康有重大危害子痫前期疾病，基于胎盘是妊娠过程中重要的内分泌器官这一事实，从胎盘类固醇激素调节母胎界面多细胞互作和母体脏器功能的角度入手，围绕“妊娠过程中类固醇激素合成和代谢紊乱如何导致子痫前期的发生发展”这一关键科学问题，系统分析子痫前期患者妊娠过程中类固醇激素合成和代谢的病理状况，并从免疫调节和表观遗传角度探寻其类固醇激素合成代谢异常的机制；进而从母胎界面多细胞互作及母体脏器血管舒缩的层面探讨类固醇激素失衡造成子痫前期病理变化的分子机制，并针对类固醇激素失衡探讨干预子痫前期的新策略。研究将揭示孕期类固醇激素失衡与子痫前期发生发展的内在联系，为探索子痫前期诊治策略提供坚实的理论基础和新思路。

项目针对子痫前期类固醇激素紊乱的原因及其导致不良妊娠结局的机制开展研究，取得如下主要研究成果：1）发现早发型子痫前期（EPE）为胎盘性激素合成失衡性疾病，患者从妊娠早中期呈现高雄低雌状态。2）揭示了持续营养压力诱发异常合体化和激素合成能力受损的机制；发现糖代谢模式与滋养层细胞命运交互调节的机制；证明EPE胎盘中缺氧刺激使Gata3的O-GlcNAc修饰水平异常增强，导致T0合成异常增加。这一系列结果提示EPE胎盘激素合成功能紊乱与营养传输和代谢的异常调节密切相关。3）发现胎盘中褪黑素和雌雄激素间的相互反馈调节维持胎盘内分泌稳态；EPE胎盘中褪黑素合成减少源于雌雄激素失衡，亦是胎盘反馈“抵抗”性激素失衡的策略；褪黑素补充可造成更加剧烈的胎盘内分泌紊乱以及胎盘/胎儿发育受损，故而不可用于子痫前期的干预。4）从母胎界面多细胞互作角度，证明T0-AR与PKA信号协调控制滋养层合体化进程；同时雌雄激素可能影响enEVTs、子宫蜕膜细胞、蜕膜NK和巨噬细胞间互作，参与调节子宫螺旋动脉改建；单细胞转录组分析发现EPE母胎界面上多种细胞亚群特性的异质性变化，提示性激素合成紊乱可能导致母胎界面局部免疫环境失调。5）从妊娠适应性调节角度发现，EPE胎盘性激素合成失衡及免疫紊乱导致母体肾脏和肝脏促凝因子a2-AP异常上调，引起母体高凝和胎盘血流灌注减少；靶向阻断a2-AP活性可有效逆转子痫前期样表型。.项目在科学理论方面取得一定的突破，发表项目标注研究论文13篇，其中多篇被遴选为期刊封面、主编重点推荐文章、Faculty Opinions推荐文章等；研究结果申请专利2项，亦为探索子痫前期预测和诊治策略提供新思路。参与项目的骨干人员有1名晋升副研究员；培养博士7名、硕士1名，出站博士后1名；仍在培养的博士生3名，硕士生2名，在站博士后1名。