VEGF相关microRNAs在早/晚发型重度子痫前期中的作用机制研究

The pathogenesis of preeclampsia is still unknown. Vascular endothelial damage theory is one of the important theories. Early onset severe preeclampsia and late onset severe preeclampsia have obvious differences in the pathogenesis , especially in the vascular endothelial damage. In previous studies, we found that there was a very close relationship between the imbalance of miRNA-126 expression and vascular endothelial growth factor VEGF in the occurrence of severe preeclampsia. To further explore the mechanism of VEGF-related microRNAs in early / late onset severe preeclampsia is the purpose of this study. This study first detects the differential expression of VEGF related miRNAs in the plasma and placenta tissue of early, late onset severe preeclampsia patients and normal maternal in order to verify that the miRNAs play the very important role in the pathogenesis of angiogenic factor loss balancing mechanism of the early / late onset preeclampsia. Significant miRNAs will be selected to further validation of the targeted regulation between these miRNAs and VEGF. And in this study also detect the apoptosis, proliferation cycle, infiltration and other biological functions of VEGF related miRNAs in human normal trophoblast, to further explore the role of miRNA in the pathogenesis of preeclampsia.

子痫前期的发病机制至今不明。血管内皮损伤学说是其重要的发病学说之一。早发型重度子痫前期在发病机制的多个环节上与晚发型重度子痫前期有明显的区别，尤其在血管内皮损伤环节。本课题组以往研究发现靶向调控血管内皮生成因子VEGF的miRNA-126表达失衡与重度子痫前期的发生有着极为密切的关系。拟在本课题中进一步探讨与VEGF相关的多种miRNA在早/晚发型重度子痫前期中的作用机制。本课题首先检测早/晚发型重度子痫前期患者及正常孕妇血浆和胎盘组织中VEGF相关miRNAs的差异表达，验证miRNA在早/晚发型子痫前期发病过程中的血管生成因子失平衡机制中的重要作用并筛选出有意义的miRNAs，进一步对VEGF与相关miRNAs的靶向调控关系，以及miRNA异常表达后滋养细胞凋亡、增殖、浸润等生物学行为的改变进行研究，深入揭示VEGF相关的miRNAs在子痫前期发病过程中的重要作用。

子痫前期（preeclampsia，PE）是妊娠期特发的严重并发症，以妊娠20周以后发生的高血压、蛋白尿、心肝肾等多脏器功能障碍为主要临床表现，是目前孕产妇和围产儿致病率和病死率的重要原因，严重威胁母婴健康。重度PE每年可造成全世界约63000例孕妇死亡，围产儿死亡风险高达16.6%。PE发病的核心为子宫螺旋动脉重塑异常与全身血管内皮系统损伤，但发病机制尚不完全明确。因此，阐明PE发病机制对寻找临床治疗的药物靶点具有非常重要的意义。本项目在前期研究基础上采用临床收集的样本筛选了血管内皮生长因子（VEGF）相关的10个miRNA在正常组织和PE组织中的差别，发现了microRNA-335存在较大差异，机制研究发现其可以影响细胞增殖、侵袭和转移，并且影响血管新生。亲环素A（Cyclophilin A，CypA）是体内重要的炎症因子。本项目通过软件分析和基因分型测定发现Cyp A rs3735481和rs9638978 的基因多态性与重度PE的发病相关。并通过检测外周血及胎盘组织中CypA的表达分析发现重度PE尤其是早发型重度PE患者外周血和胎盘组织中CypA的表达水平均显著升高。CypA表达水平可反应病情的严重程度，或可成为重度PE的预测与病情评价的重要血清标志物。这些围绕PE开展的研究为其发病机制阐明和临床治疗提供了基础依据。