上皮钠通道（ENaC）调节分娩中子宫收缩及早产的作用机制研究

Preterm labor is the major cause for perinatal period death, which can result in dysfunction in many organs. The cause for preterm labor is preterm initiation of myometirum contraction. However, the mechanism of parturition initiation remains elusive. ENaC was found to functionally express in endometrium, which can be activated by both protease and mechano-force. Moreover, activation of ENaC in endometrium increases the PGE2 release via up-regulating the expression and activity of COX-2. It is reported that PGs play a central role in uterine contraction and the synthetase of PGs largely express in the endometrium, which can release enough PGs. In the early stage of parturition, the uterine contraction induced by oxytocin may activate ENaC, since ENaC is mechano-force activated cation channel. Taken all these together, we hypothesize that endometrial ENaC can be activated by uterine contraction induced by oxytocin; activation of ENaC can increase the release of PGE2, which acts on myometrium, leading further enhancement of uterine contraction. In this project we firstly investigate the involvement of ENaC in uterine contraction and subsequently the process of parturition via smooth muscle contraction system and animal model. Furthermore, we will investigate the pathway for the regulation of ENaC on PGE2 via in vitro experiments. Finally, the expression profile of ENaC will be checked in mice of preterm labor model and we will also explore whether ENaC inhibitior amiloride can improve the preterm labor in PTL animal model. This project will demonstrate the role of ENaC in parturition, and shed light on development of new drugs for treatment of preterm labor.

早产是围产期婴儿致死的主要原因，并能导致新生儿多种器官出现障碍。早产的原因是子宫肌层提前进入收缩状态，由静止状态向分娩状态转变。目前分娩的触发机制并不清楚。已知前列腺素PGE2在分娩过程中对刺激子宫收缩起着重要的作用。我们最新的研究表明，子宫内膜上皮中的ENaC被激活后可以上调前列腺素合成酶COX-2的表达，并增加PGE2的释放。由于ENaC可以通过机械力激活，我们假设：在分娩早期催产素所引起的子宫收缩可以激活ENaC, 进而上调COX-2并增加PGE2的释放，刺激子宫肌层收缩，从而参与分娩过程，而ENaC的过表达或功能的过分激活，可能导致早产。本课题采用内膜上皮细胞证明ENaC对COX-2/PGE2的调控，用平滑肌收缩实验验证ENaC通过COX-2/PGE2对子宫收缩的调节作用，通过小鼠早产模型研究ENaC在早产中的作用。本研究将首次阐明ENaC参与分娩可能导致早产的作用机制。

早产是新生儿死亡的主要原因，然而其机制并不清楚，目前并没有有效的治疗方法。虽然子宫收缩被认为是分娩与早产的迹象，但是这种机械信号是如何被转导成细胞因子的改变以及子宫收缩如何导致分娩这一过程的机制仍然不清楚。本课题中，我们证明了机械敏感的上皮钠通道参与调节了子宫收缩，打开了分娩所必需的细胞炎症因子的开关。子宫上皮钠通道的表达可以被子宫牵拉或者分娩过程中上升的一种糖皮质激素---皮质醇所上调。同样在RU-486引起的早产模型小鼠、早产人的血中以及早产的胎盘中，上皮钠通道的表达都要对正常组高。大数据分析显示，分娩或者早产组中，上皮钠通道与分娩相关的炎症因子具有比未分娩组更强的相关性。上皮钠通道抑制剂或者基因敲减可以推迟RU486所引起的早产。目前的发现揭示了上皮钠通道在分娩与早产中的重要作用。实验结果表明血液中上皮钠通道以及相关的炎症因子可以作为诊断早产的依据，ENaC的抑制可能成为预防突发性早产的一种可行的治疗手段。