蜕膜NK细胞表观遗传学改变在子痫前期发病中的作用机制

Preelampsia is one of the major reasons of maternal and perinatal morbidity and mortality. It threatens the health of both mothers and infants. The poor invasion of extravillous trophoblasts and abnormal uterine spiral artery remodelling are related to the pathogenesis of preeclampsia. The natural killer (NK) cells play important role in the process, but the mechanism is not clear yet. We propose to focus on the NK cells, especially the epigenetics of decidual NK cells. Complex markers immunofluorescent testing and flow cytometry will be used to decide the origin of the decidual NK cells in mouse model at different gestational age and in different tissues. Epigenome wide association study (EWAS) will be used to compare NK cells from different tissues. And the function of decidual NK cells from preeclampsia individuals（mouse model or patients）and healthy controls will be compared as well. Bioinformatic analysis and verification made by QRT-PCR and western blot at mRNA level and protein expression will be used to find the key differential genes. On these bases, in vivo animal trials will be used to analyze the role of key differential genes in the regulation of decidual NK cell differentiation, the abnormal trophoblasts invasion and poor placental vascular remodelling. And therefore explain the pathological mechanism of the occurrence and development of preeclampsia. This project will help clarifying the role of NK cell in preeclampsia, and provide scientific basis for finding the potential molecular targets for the prevention and treatment of preeclampsia.

子痫前期是导致孕产妇和围产儿死亡的主要原因之一，严重威胁母婴健康。子痫前期发病与绒毛外滋养细胞侵袭不良及子宫螺旋动脉重塑异常有关，自然杀伤细胞（NK细胞）在此过程中具有十分重要的作用。本申请研究以NK细胞为研究对象，拟通过EWAS比较子痫前期与正常对照的蜕膜NK细胞的表观遗传改变，并通过生物信息学分析及后续验证找出关键差异基因；随后通过动物实验研究关键差异基因在介导NK发育异常、及其进一步诱导滋养细胞侵袭力异常，以及胎盘血管重塑不良并最终导致子痫前期发生、发展的病理机制。这一项目将有助于阐明NK细胞在子痫前期发病中的机理，并为寻找防治子痫前期的分子靶标提供科学依据。

子痫前期是导致孕产妇和围产儿死亡的主要原因之一，严重威胁母婴健康。子痫前期发病与绒毛外滋养细胞侵袭不良及子宫螺旋动脉重塑异常有关，自然杀伤细胞（NK细胞）在此过程中具有十分重要的作用。本研究建立了PE动物模型，获得了不同组织与蜕膜的NK细胞。通过EWAS比较了子痫前期孕妇与正常对照的胎盘的表观遗传改变，并通过生物信息学分析及后续验证找出关键差异基因。研究发现，PE患者胎盘较正常胎盘在基因组部分区域存在明显的低甲基化，低甲基化水平在胎盘不同部位没有差异。研究共发现差异甲基化基因88个，与细胞间通讯、免疫反应、血小板激活和突触传递通路显著相关。研究结果为PE发病机制的阐释提供了依据，为靶向干预提供了可能。