miR-128对NRF2的调控及其在子痫前期发病的作用机制研究

Preeclampsia and fetal growth restriction are considered as "placental derived diseases". Placental local oxygen concentration and trophoblast biological behavior may be associated with the pathogenesis of preeclampsia, but the specific mechanism remains unclear. NRF2 is a key antioxidant factor. Our previous study demonstrated that the up-regulation of NRF2 in the placenta of fetal growth restriction. Hypoxia and oxidative stress may be involved in the pathogenesis of fetal growth restriction through regulation of NRF2. However, studies on the relationship between the NRF2 expression level and the pathogenesis of preeclampsia are few and the results are inconsistent. NRF2 is regulated by microRNAs in hypoxia and oxidative stress environment. Bioinformatics analysis predicts that NRF2 may be a target gene of miR-128. So we hypothesis that miR-128 may affect the trophoblast biological behavior through regulation of NRF2, and play an important role in the pathogenesis of preeclampsia. This project intends to study the regulation of miR-128 on NRF2 and trophoblast biological behavior. The purpose of this study is to investigate whether miR-128 can affect the trophoblast biological behavior through regulation of NRF2, and the possible mechanism involved in the pathogenesis of preeclampsia. The conclusion may provide a new evidence for the explaination and treatment of preeclampsia.

子痫前期与胎儿生长受限被认为是“胎盘源性疾病”，胎盘局部氧浓度的变化及滋养细胞的生物学行为可能与子痫前期的发病有关，但具体机制不详。NRF2是抗氧化反应的关键转录因子，我们前期研究发现NRF2在胎儿生长受限胎盘表达上调，缺氧及氧化应激可能通过调控NRF2参与胎儿生长受限的发病，但NRF2的表达与子痫前期发病关系的研究较少，结果亦不一致。缺氧及氧化应激反应中NRF2的表达受microRNAs的调控，生物信息学分析预测NRF2可能为miR-128的靶基因。据此我们推测，miR-128可能通过调控NRF2，影响滋养细胞的生物学行为，参与子痫前期的发病。本项目拟通过子痫前期胎盘及绒毛外滋养细胞系，研究miR-128对NRF2的调控，及对滋养细胞生物学行为的影响。探讨miR-128是否通过调控NRF2的表达对滋养细胞的生物学行为产生影响，参与子痫前期的发病，为子痫前期发病机制研究提供新证据。

胎盘滋养细胞生物学行为的异常及核因子相关因子2（nuclear factor, erythroid 2 like 2，NRF2）表达的改变被认为与子痫前期的发病有关，但相关机制研究较少，结果亦不一致。本研究明确HIF1α及NRF2在子痫前期胎盘中表达上调，通过GEO数据库高通量测序、芯片数据的筛选，发现子痫前期胎盘中miR-101存在差异性表达，相关性分析推测miR-101可能是子痫前期胎盘中调控NRF2表达的上游因子。体外实验发现，过表达miR-101可促进滋养细胞增殖、抑制凋亡并增强侵袭能力，沉默miR-101则起着反效果，证实miR-101对滋养细胞生物学行为的影响。机制上，NRF2被证实为miR-101的下游靶基因，miR-101对NRF2及下游抗氧化基因的表达有着负向调控作用，推测miR-101可能通过调控NRF2影响滋养细胞生物学行为；进一步研究发现过表达及沉默NRF2对滋养细胞生物学行为及下游抗氧化基因表达的调控作用与miR-101相反，通过过表达及沉默NRF2对miR-101过表达及沉默的“挽救实验”明确了miR-101通过调控NRF2的表达影响滋养细胞的生物学行为。综上，本研究从在体-细胞-分子三方面初步探索了miR-101对NRF2的调控及其在子痫前期发病的作用机制。