PAPP-A调控胎盘IGF轴影响FGR的分子机制研究

胎盘是母胎界面物质交换的唯一渠道，保证了胎儿正常生长发育。部分胎儿生长受限(FGR)与胎盘滋养层细胞基因表达异常密切相关。妊娠相关血浆蛋白(PAPP-A)是胎盘分泌的蛋白酶，在妊娠妇女中大量增加且被pro-MBP共价抑制，通过特异性切割胰岛素样生长因子结合蛋白(IGFBPs)定向调节血清胰岛素样生长因子(IGFs)浓度和调控胎盘功能。既有研究表明FGR中PAPP-A浓度显著降低，但具体机制未被阐明。据此，本项目计划对常规妊娠检查的剩余血清进行PAPP-A、IGFs等相关分子的浓度测定，结合体外酶切效率检测，明确其对FGR的预测能力；对FGR与正常胎盘组织行多组学联合分析，探索PAPP-A通过IGF轴影响胎盘发育的调控网络；建立血清内源性蛋白提取方法，辅以传统重组蛋白表达，以PAPP-A及其复合物为对象进行结构生物学研究，明确PAPP-A的原子结构与抑制机制，在分子水平阐述FGR产生的机理。

The placenta is the only maternal-fetal interface for material exchange, ensuring the normal growth and development of the fetus. Asymmetrical fetal growth restriction (FGR) is closely related to abnormal gene expression of placental trophoblast cells. Secreted by placenta, pregnancy-related plasma proteins (PAPP-A) protease increases significantly in pregnant women. Covalently inhibited by pro-MBP, PAPP-A specifically cleaves IGFs-bin ding proteins (IGFBPs) and influences serum IGFs concentration to regulate placental function. Previous studies proved the concentration of PAPP-A is considerably reduced in FGR pregnancy, but the underlying mechanism remains unknown. . Accordingly, this project expects to clarify the ability of PAPP-A to predict FGR by measuring the concentration of PAPP-A, IGFs and other related molecules in the remaining serum of routine pregnancy tests, combined with the in vitro enzyme digestion efficiency test. We would like to perform multi-omics analysis to explore the regulatory network that how PAPP-A affects placental development through the IGF axis. At the same time, we also plan to establish serum endogenous protein extraction methods and supplemented with conventional exogenous recombinant protein purification, and conduct structural biology studies on PAPP-A and its complexes. The goal of the project is to clarify the atomic structure and inhibition mechanism of PAPP-A, and to explain the underlying mechanism of FGR at the molecular level.