miR-193b-3p-miR-31-5p-RIMS3调控网络在子痫前期发生中的作用及机制研究

Preeclampsia (PE) is a leading cause of maternal mortality worldwide. microRNAs are considered to be important factors during placentation. The abnormalities of these epigenetic regulation contribute to the progression of PE. We have detected miR-193b-3p-miR-31-5p were up-regulated and RIMS3 was down-regulated in PE placenta. miR-193b-3p decreased the migration and proliferation of trophoblast cells in our previous study. RIMS3 was observed as a co-target of miR-193b-3p-miR-31-5p in trophoblast cells. In current study, we will study the function and mechanism of a regulatory network of miR-193b-3p-miR-31-5p-RIMS3 in trophoblast cells. We will study the role of RIMS3 in trophoblast cells. We will also study other targets which were synergistically targeted by miR-193b-3p-miR-31-5p and their function in PE placeta. Finally we will explore the role of miR-193b-3p-miR-31-5p-RIMS3 in early pregnancy through Trophoblast stem cells (TSC) Transplantation and mouse model. This will be beneficial to PE therapeutics.

子痫前期(PE)对孕产妇、胎儿及新生儿危害巨大。已有报道，microRNA调控紊乱在PE发生中扮演关键作用，而多个miRNAs如何协同参与这一过程却知之甚少。我们前期研究显示PE胎盘上调表达的miR-193b-3p-miR-31-5p，协同作用于靶基因RIMS3，形成表达调控网络，且其表达水平影响胎盘滋养层细胞功能。本课题拟回答：miR-193b-3p-miR-31-5p-RIMS3调控网络如何参与胎盘形成过程导致PE发生。研究将以临床胎盘组织和细胞系/原代培养细胞为基础，利用免疫共沉淀、质谱等技术，首先阐明上述调控网络的作用方式与功能机制；其次利用转录组测序等技术，筛选两个miRNAs协同作用的其它靶基因及相关信号通路；最后通过滋养层干细胞裸鼠侵袭及小鼠动物模型，探讨上述网络异常对早期妊娠及PE相关临床表型的影响。此研究结果有望为PE的诊疗提供潜在新靶点和理论依据。

子痫前期严重危害孕产妇及胎儿生命健康。本课题拟回答：miR-193b-3p-miR-31-5p-RIMS3调控网络如何参与胎盘形成过程导致PE发生。依托本项目资金支持，我们发现：① miR-193b-3p与miR-31-5p是正常健康妊娠孕妇与子痫前期孕妇的关键差异miRNA，且与子痫前期的主要临床指标具有紧密相关性。② miR-193b-3p抑制滋养层细胞的迁徙侵袭。③ miR-31-5p或可作为子痫前期生物学预测指标。④ RIMS3在子痫前期胎盘中表达下调，双荧光素酶证实：RIMS3是miR-193b-3p与miR-31-5p的共同靶基因。近年来microRNA被证实与多种疾病密切相关，包括恶性肿瘤、妊娠相关疾病如子痫前期等；鉴于滋养层细胞与肿瘤细胞相似的生物学特性，本项目研究结果有可能为子痫前期的防治提供进一步的理论依据和新的干预靶点。