Tim-3信号通路异常调控uNK细胞分泌perforin影响反复着床失败患者子宫内膜容受性的分子机制

Repeated implantation failure (RIF) mostly caused of low endometrial receptivity is a challenge need be resolved in in-vitro fertilization and embryo transfer (IVF-ET) cycles. Balanced maternal-fetal immunity is vital to embryo implantation and successful pregnancy while aberrant releasing perforin by uNK cells might disturb this balance and lead to RIF. Tim-3 showing low expression in RIF patients with obscure molecular mechanisms, can inhibit the function of uNK cells as well as the expression of perforin, CEACAM1 is one important chaperone protein of Tim-3, and IL-2 stimuates CEACAM1 secretion. In our preliminary research, down-regulated Tim-3 and up-regulated perforin, CEACAM1 and IL-2 expressions were found in patients suffering RIF during implantation period, while there was no change of FasL, IFNγ and uNK number. Based on the previous studies, this project would begin with Tim-3 and apply various biochemical approaches to elucidate the functions of uNK cells, perforin and Tim-3 pathway in manipulating the endometrial receptivity by investigating it’s downstream targets and probing it’s interactions with uNK cells and perforin. This study would be of great scientific and social significance in identifying novel drug targets, providing new insights into the regulatory mechanisms to endometrial receptivity and the pathology into impaired reception of endometrium in RIF patients.

胚胎反复着床失败（RIF）是IVF-ET中亟待解决的难题，主要与子宫内膜容受性低下相关。母胎界面免疫失衡是降低内膜容受性的重要病因，其中uNK细胞通过perforin毒性发挥主要作用。Tim-3/Gal-9信号通路调控uNK细胞功能及perforin分泌，但机制不详。我们前期研究发现RIF患者着床期子宫内膜Tim-3下调，Gal-9不变，伴侣蛋白CEACAM1及IL-2上调，uNK细胞数量不变而perforin增加，提示Tim-3表达下降增强uNK细胞分泌perforin与RIF相关。本项目将在前期研究基础上以Tim-3为切入点，运用分子生物学方法、细胞生物学方法和实验模型，重点探讨Tim-3/CEACAM1通路异常调控uNK细胞分泌perforin在影响子宫内膜容受性中的作用，这一研究对于阐明RIF的发病机制，发现新的药物靶点具有重要的理论意义和临床价值。

胚胎反复着床失败（RIF）是IVF-ET中亟待解决的临床难题。主要与子宫内膜容受性低下相关。大通量分析发现RIF患者着床期内膜中参与免疫反应/炎症、代谢/生物合成及细胞周期的基因异常变化。机制研究验证了Tim3通过配体HMGB1调节uNK毒性，并引起上皮细胞黏附功能改变，影响子宫内膜容受性；PECAM1/TGFβ1、AIF-1/TNFα、CDYL/CTNNB1、S100PPIBF1/IL6/p-STAT3、及uNK活性的变化会影响子宫内膜黏附，迁移、增殖、凋亡、蜕膜化、免疫异常，从而造成子宫内膜容受性异常，抑制胚胎着床。本研究聚焦子宫内膜容受性的发病机制，探讨的潜在因素，为解决RIF患者子宫内膜容受性低下、探索新的分子标志物及治疗靶点、提高IVF妊娠率提供了新的思路与证据。