microRNA-125b调节母胎界面VEGF表达与复发性流产病理发生关系的研究

Recurrent pregnancy loss (RPL) is a common pregnancy complication, and affects about 5% of pregnancy. Although some know causes, such as, genetic problem, endocrine issue, and abnormal uterine structure, can lead to RPL, there are still about 50% of RPL having no identified causes. Also, there is no effective treatment for these unknown reason RPL patients. Studies had shown that microRNA plays key roles in the disease development, and recent microRNA profile screening studies showed that the miR-125b was upregulated in the villi from RPL patients. Our preliminary data confirmed the upregulation of miR-125b in the villi of PRL patients. Meantime, we found it also upregulated in the deciduas. Also, VEGF, the down stream target gene of miR-125b, is abnormally expressed in both villi and deciduas in the RPL patients. Our preliminary data show that, the trophoblast invasion ability was inhibit when overexpress miR-125b in HTR8 cell line, and there is embryos loss in early pregnancy when placental specific overexpressed in mouse embryos. However, the relationship of exact location (placenta or endometrium or both), time frame of miRNA-125b over expression, and the miRNA-125b and VEGF pathway with the disease development of RPL is unknown. Also, whether inhibiting miRNA-125b pathway could be a curative way for RPL is unknown. So, in this proposal, in vitro cell culture experiments, controllable in vivo placenta- and endometrium- specific overexpression of miR-125b were used to investigate the involvement of miR-125b and its regulation of VEGF pathway with the disease development of RPL by overexpress miR-125b from different temporal (before pregnancy, early-, mid- and late- pregnancy) and spatial (placenta-, endometrium- or maternal origin) combination. In addition, the miR125b inhibitor will be tried by investigator developed placenta-specific delivery with nanoparticles to treat RPL, and investigating the possibility as a treatment drug. The results from this proposal will provide new target and theory basis for preeclampsia diagnosis and treatment.

复发性流产（RPL）是常见妊娠并发症之一，影响5％的妊娠，至今仍有50%的RPL病因不明，此类患者尚无有效治疗手段。报道发现miR-125b在病因不明RPL患者绒毛中表达上调，与我们验证结果一致。我们还发现miR-125b在蜕膜表达上调，其靶基因VEGF表达异常。并且初步miR-125b体外过表达抑制滋养细胞侵润功能、胎盘特异性过表达出现早期胚胎丢失。但具体诱发RPL的miR-125b病源位置、时间、是否通过调节VEGF通路参与RPL发生和抑制其通路能否治疗RPL等，均不清楚。因此，本研究用体外细胞模型结合体内可控的胎盘和子宫内膜特异性基因过表达手段，阐明miR-125b在不同时（妊娠不同时期）空（胎盘、子宫）组合上过表达与RPL发病的关系，并用胎盘特异性投递手段给予miR-125b抑制剂治疗RPL模型，探讨miR-125b成为RPL治疗靶点的可能性，为RPL的预防和诊治提供靶和理论依据。

复发性流产（RPL）是常见妊娠并发症之一，影响5％的妊娠，至今仍有50%的RPL病因不明，此类患者尚无有效治疗手段。通过本研究发现miR-125b在病因不明RPL患者绒毛中表达上调。通过在体动物实验特异性胎盘滋养细胞过表达miR-125b可以出现流产症状。其主要病理表面为导致滋养细胞侵入能力下降，进一步分析发现miR-125b可以导到VEGFA表达下调，可能是导致滋养细胞侵入能力下降以及胎盘血管系统不健康的原因。明确滋养细胞miRNA-125b异常可导致流产后，进一步开发出了滋养细胞靶向药物递送方式，为下一步进行治疗验证提供工具。同时开发了液体活检，为早期快速精准分析滋养细胞功能以及对复发流产早期检查与预测提供的基础。通过本研究，明确了miRNA-125b为复发流产的病因之一。同时开发了进一步研究的两项工具，为复发流产的深入研究提供了有效的手段。