CD44/c-Src调控PECAM1低表达影响反复着床失败患者子宫内膜容受性的分子机制

Recurrent implantation failure (RIF), mostly caused by low endometrial receptivity, is a clinical challenge needed to be eagerly resolved. Our previous study has found that the low expression of PECAM1 affected the endometrial receptivity of RIF patients. And the expression pattern of CD44 in endometrium was consistent with that of PECAM1 in different stages of menstruation. Moreover, the expression levels of CD44 and its classical downstream factor c-Src were decreased in RIF patients as well. After interfering the expression of CD44 in endometrial carcinoma cells, the expression of c-Src and PECAM1 decreased significantly. Whether CD44/c-Src regulates endometrial receptivity via PECAM1-dependent mechanism remains unknown. This study will further reveal the effect of CD44 on endometrial receptivity from the cellular level, which will be verified by conditional uterine CD44 knockout female mice. We will investigate the effect of CD44/c-Src pathway in regulating the expression of PECAM1 and clarifying its molecular mechanism on modulating endometrial receptivity. By performing rescue experiment we will testify the effect of critical molecules in this signal pathway on improving endometrial receptivity. By detecting the newly target molecules in uterine fluid we will discover the markers of endometrial receptivity. This study would be of great theoretical significance and clinical value for elucidating the pathogenesis of RIF and finding novel drug targets for improving endometrial receptivity.

子宫内膜容受性低下所致反复着床失败（RIF）是目前辅助生殖技术临床难题。我们研究发现：PECAM1低表达影响RIF患者子宫内膜容受性；CD44与PECAM1在月经周期动态表达模式一致；CD44及其经典下游因子c-Src在RIF子宫内膜中表达亦降低；干扰人子宫内膜癌细胞CD44表达，c-Src和PECAM1表达下降。那么，CD44/c-Src是否通过调控PECAM1低表达而影响RIF患者子宫内膜容受性？尚待深入研究。本项目将进一步从细胞水平揭示CD44对子宫内膜容受性的影响，并以条件性敲除CD44小鼠验证；通过探讨CD44/c-Src调控PECAM1表达的信号传导通路，阐明其影响内膜容受性的分子机制；通过补救实验，验证该通路中关键分子在改善内膜容受性中的作用；通过检测宫腔液中游离靶分子，探寻内膜容受性标志物。本项研究对于阐明RIF发病机制、发现改善内膜容受性药物靶点具重要理论意义和临床价值。

子宫内膜容受性低下所致反复着床失败（RIF）是目前辅助生殖技术临床难题。本项目研究阐明RIF患者分泌中期低表达的CD44v3通过下调人子宫内膜间质细胞的增殖和蜕膜化功能，从而抑制子宫内膜容受性，部分揭示了RIF患者子宫内膜容受性低下的病理机制。本项目同样关注其他可改善子宫内膜容受性的新药物靶点及预测子宫内膜容受性的新标志物，并发现RIF患者分泌中期子宫内膜低表达的PIBF1可能通过下调IL6/p-STAT3信号通路，抑制HESCs的增殖及蜕膜化，影响RIF患者子宫内膜容受性。本项研究对于阐明RIF发病机制、发现改善内膜容受性药物靶点具重要理论意义和临床价值。