子痫前期新型预测标志物EBI3的鉴定及其致病作用的分子机理研究

子痫前期依据发病时间分为早发型（EOPE）和晚发型子痫前期（LOPE），因其致病机理复杂，临床缺乏特异性预测方法。申请人前期研究EOPE的胎盘源性致病因子，通过单细胞转录组测序技术和基因芯片技术联合分析筛选出一组潜在适用于EOPE诊断和预测的标志物。进一步预研究结果表明：潜在标志物EBI3在EOPE孕妇的外周血循环水平显著升高，且与孕妇的尿蛋白和血尿酸呈现正相关趋势；生物信息学分析提示EBI3可能促进Th1+细胞分泌IL-12进而激活肾小管系膜细胞的JAK-STAT信号通路，导致其异常增生引起肾功能损伤，促进EOPE的发生发展。我们在前瞻性临床观察中也证实了上述结果。由此提出科学假说：EBI3是引起孕妇EOPE临床表现的关键调控因子，并可作为EOPE的特异性诊断和预测标志物之一。本项目将深入探讨EBI3引起EOPE临床表征的机制，为EOPE的预测和诊断提供新的生物标志物和潜在治疗靶点。

Preeclampsia can be classified into early-onset (EOPE) and late-onset preeclampsia (LOPE) based on the time of the disease onset. Due to its complex pathogenesis, there is still no specific predictive method.Our recent work aim to identify the placental factors that cause preeclampsia. With the strategy of combinative analysis of single-cell RNA sequencing and transcriptomic profiling, we have identified several potential biomarkers for EOPE.Experiments with patient blood plasma further indicated that the circulating level of the potential biomarker EBI3 was increased over two times in EOPE patient and showed trends of positive-correlation with uric acid and proteinuria levels.Bioinformatics analysis suggested that EBI3 promotes the secretion of IL-12 from Th1+ cells, which further activates the JAK-STAT signaling pathway in mesangial cells, leading to hyperplasia and renal function injury, and promoting EOPE. We also confirmed the above results in prospective clinical observations. Therefore, we suggest that EBI3 is a key regulatory factor that causes the clinical manifestations of EOPE in pregnant women and can be used as one of the specific diagnostics and predictive markers of EOPE.In the current project, we plan to explore the deep mechanism of EBI3 causing clinical manifestations of EOPE, and hence to provide new biomarkers and potential therapeutic targets for the prediction and diagnosis of EOPE.