子宫内膜上皮细胞SGLT3a介导蜕膜相关旁分泌效应及其机制研究

Uterine decidualization plays an important role in pregnancy establishment and maintenance. During the implantation phase, a signal from the uterine cavity first induces the secretion of paracrine factors by the endometrial epithelial cells, which in turn mediates the decidualization of stromal cells. However, few studies have identified the key “sensor” molecules in endometrial epithelial cells that when activated cause the release of paracrine factors. There is evidence that sodium-glucose linked transporter 3a (SGLT3a) acts as a “sensor” molecular in some kinds of cell. Our pre-experiment work has shown that SGLT3a is expressed in mouse endometrial epithelial cells during the implantation phase and is involved in decidualization. The activation of SGLT3a can induce extracellular Ca2+ influx in endometrial epithelial cells and promote prostaglandin E2 secretion. Thus, we intend to further study role of SGLT3a in decidualization-associated paracrine of endometrial epithelial cells and the mechanisms involved through in vitro and in vivo experiments. In this project, we will focus on SGLT3a, verify the characteristics of SGLT3a as a sensor molecule in endometrial epithelial cells, study the mechanisms by which it induces decidual- associated paracrine effects, and prove the role of SGLT3a-inducing paracrine effects in the decidua. The aim is to reveal the functional relationship between endometrial epithelial cells and stromal cells in decidualization, which could provide a new clue for the etiology and pathological mechanism of infertility.

蜕膜对妊娠建立与维持具有重要作用。在着床窗口期，来自宫腔侧的信号诱导内膜上皮细胞分泌蜕膜相关旁分泌因子，介导基质细胞蜕膜。然而，触发内膜上皮细胞旁分泌效应的上游感受器分子及其作用机制尚未完全阐明。钠-葡萄糖协同转运体SGLT3a在一些细胞中表现出感受器分子特性。我们预实验发现：子宫内膜上皮SGLT3a参与了基质细胞蜕膜，激活SGLT3a可引起子宫内膜上皮细胞外Ca2+内流并促进前列腺素PGE2分泌。基于此，申请者拟通过体内外实验，进一步研究子宫内膜上皮细胞SGLT3a介导蜕膜相关旁分泌的效应及其机制。本项目将研究子宫内膜上皮细胞SGLT3a的感受器分子特性，阐释SGLT3a介导蜕膜相关旁分泌效应的机制，并验证SGLT3a介导的子宫内膜上皮旁分泌效应在蜕膜中的作用。本项目以SGLT3a为研究立足点，阐释蜕膜过程中子宫内膜上皮-基质细胞的功能联系及机制，可为女性不孕的病理机制研究提供新线索。

本项目通过在体实验和体外实验，利用细胞分子生物学技术，结合激光共聚焦显微技术和异体胚胎移植等技术，研究子宫内膜上皮细胞SGLT3a激活诱导基质细胞蜕膜化的相关旁分泌效应及机制。我们的研究结果提示，SGLT3a在围着床期小鼠子宫内膜上皮细胞高表达，雌、孕激素可协同促进SGLT3a表达。SGLT3a不具有葡萄糖转运功能，但具有感受器分子特征，其激活引起细胞膜电位、发生Na+负载的去极化，进而使胞外Ca2+内流，上调Cox2，促进PGE2表达释放，PGE2通过旁分泌方式诱导基质蜕膜化，并影响植入后胚胎发育。本研究以感受器分子SGLT3a为研究切入点，从一个新的视角对子宫内膜上皮蜕膜化相关旁分泌效应的上游分子机制进行探索，进一步揭示着床过程中子宫内膜上皮与基质细胞间的功能联系。