蜕膜反应缺陷在人子痫前期发病中的作用及其分子机制

Preeclampsia (PE) has severe adverse impact on both mother and child. Despite intensive research, a full understanding of the pathogenesis of preeclampsia remains elusive. What we can assure is that placenta plays a central role in PE pathogenesis. Because preeclampsia originates in the placenta and ends with the delivery and removal of placental tissue. Several mechanisms have been implicated in the etiology of preeclampsia, including defects in vascular modeling, immunological abnormality, deficiency of extravillous trophoblast invasion, cell apoptosis, etc. During our research upon the conditional knockout (CKO) mice of liver receptor homolog-1 (Lrh-1), we found unexpectedly that disability of decidualization might be an important reason except the above factors.Decidua plays an important role in the establishing of placenta. We demonstrated that the decidualization defects happened to our CKO mice caused the superficial invasion of extravillous trophoblasts，impaired spiral artery remodeling, which are hallmarks in preeclampsia. The mechenism of decidualization is quite similar between humans and mice. So we infer that the defection in decidualization might cause human PE. Therefore this application is going to collect the deciduas from the delivery women and study the transcription profiles of the deciduas of PE by the way of RNAseq, combining with in vitro cell culture，siRNA, chromatin immunoprecipitation and other techniques, to explore the relationship and mechanism of decidualization with PE, so as to provide new views for gestational health care.

子痫前期(preeclampsia,PE)对胎儿和母体造成严重影响。尽管人们对其进行了广泛的研究，但其发病机理仍然不是很清楚,可以肯定的是胎盘在发病过程中起核心作用。一般认为，PE病人胎盘不正常有如下原因：血管形成不足，免疫异常，绒毛外滋养细胞入侵不足，细胞凋亡等。而我们前期在研究肝受体类似物（liver receptor homolog-1）条件基因敲除（CKO）小鼠的妊娠中意外发现除上述因素外，蜕膜反应障碍可能也是一个重要原因。蜕膜对于胎盘的建立发挥着重要的作用。CKO小鼠由于蜕膜化缺陷，出现了胎盘侵入减小,螺旋动脉重建受阻等PE症状。人和小鼠的蜕膜机制非常类似，因此，申请人认为蜕膜化缺陷将导致人类PE的发生。本申请拟收集产妇蜕膜组织并对其进行全方位的转录组分析（RNAseq）,结合体外培养，siRNA,染色质免疫共沉淀等技术，揭示蜕膜化对于PE的作用及其机制，为孕期保健提供新的见解。

子痫前期(preeclampsia, PE)发病率高，对胎儿和母体影响严重。目前多数研究从胎盘着手研究发病机制。我们经过多年的努力，研究了多个和胚胎着床相关的分子在PE 患者蜕膜中的表达及其作用，发现这些分子在子宫内膜的蜕膜中表达量降低，影响到蜕膜化，从而参与PE的发病。为了进一步从整体上理解PE发病机制, 我们根据项目的研究内容及研究方案，收集产妇的蜕膜组织进行了转录组测序（RNAseq）。结果发现, PE蜕膜中的转录组和正常妊娠组相比发生了明显改变。其中参与糖酵解/糖异生和HIF-1信号通路，并在癌细胞中显著上调的基因：ENO2，PGK1和HK2，在PE蜕膜中表达明显降低。另外我们筛选出23个核心调节基因，其中包括三对真假基因BNIP3 / BNIP3P1，HK2 / HK2P1和PGK1 / PGK1P2 / PGK1P1。对于以上结果我们进行了深入地功能研究。此外我们在项目开展期间还对COX2、 SP1/P300在PE发病过程中的作用及其机制进行了深入的研究， 发现它们在PE患者蜕膜内表达降低，体外实验表明这些基因的降低影响到了子宫内膜基质细胞的蜕膜化从而参与了PE的发病。项目的开展有利于理解PE的发病机理，为孕期保健提供新的见解。