IFN-λ介导围着床期母胎界面建立的分子机制研究

Successful implantation relies on the mature materno-fetal Interface during the window of implantation. A complex cross-talk among series of hormone and cytokines is included in the process of implantation. IFN-λ was discovered as a novel member of IFN family. It has been shown to predominantly act on promoting immune tolerance, but few investigations have been performed to assess its effect on embryo implantation. Based on our former researches, the expression of IFN-lambda in endometrium of infertile patients was significantly lower than that of control group. In additional，it was shown that the expression of IFN-λ increased gradually during peri-implantation process and lead to regulating the secretion of receptivity factor and activation STAT-Fas signaling pathway. It suggested IFN-λ may play crucial roles in affecting receptivity of endometrium. This study intends to combine clinical cases and molecule mechanism in order to parse the relationship of expression of IFN-λ and the pregnancy outcome, to construct the gene regulation network of embryo implantation correlated with IFN-λ, to comprehend the key molecular pathway mediated by IFN-λ. The function exploration to the adjustment of endometrial receptivity mediated by IFN-λ will be conducive to reveal the connotation of maternal and fetal immune tolerance during embryo implantation, and to explore the assistant intervention methods for uterine receptive state and a precise scheme for individual embryo transfer.

胚胎着床的成功依赖于围着床期母胎界面建立，其中涉及多种激素和细胞因子的协同调控。IFN-λ是干扰素家族的新型成员，据报道IFN-λ与免疫耐受的调节相关，但其在胚胎植入方面的功能未见报道。本研究对临床胚胎着床障碍患者种植窗口期子宫内膜样本检测发现，其IFN-λ的表达显著低于对照组。进一步研究发现，子宫组织中IFN-λ的浓度在胚胎植入过程中持续增高，其表达与内膜细胞容受及炎性因子的分泌、STAT-Fas通路的激活相关。本研究推测IFN-λ是评价围着床期内膜容受态的标志分子，其介导母胎界面建立的分子机制亟待探索。本研究拟结合临床和基础研究，解析围着床期IFN-λ的表达机制与妊娠结局的相关性，构建IFN-λ介导的子宫内膜容受态建立基因调控网络，阐明IFN-λ调控下游关键信号通路。本研究对IFN-λ在围着床期功能的探索，有助于揭示胚胎种植时期母胎免疫耐受的内涵，为个体化胚胎移植提供精准方案。

胚胎植入失败是辅助生殖技术发展面临的重大难题。免疫治疗已经普遍用于预防子宫容受性不足或免疫失衡引起的复发性流产疾病。许多容受/免疫调节因子现在被认为在胚胎-母体界面上起着至关重要的作用。然而目前公认的评价内膜容受态的标记物十分匮乏，相关的机制的研究仍待深入探讨。此项研究中，我们证实了新型干扰素λ在IVF-ET周期反复着床失败妇女的子宫内膜组织中的表达异常低于对照组患者。进一步通过基因组学和分子生物学手段，发现在人类子宫内膜细胞中，雌激素通过其受体结合在干扰素λ启动子上游雌激素激活元件上，直接诱导干扰素λ的产生。后续研究利用高通量测序法，获得并验证了干扰素λ下游396个靶基因，其中包括一批经典和潜在的容受因子和炎性因子。利用干扰素λ基因敲除型内膜细胞系开展细胞迁移和胚胎黏附实验，提示干扰素λ在调整内膜炎性反应，子宫受容态及相关母胎界面分子事件等方面均发挥作用。此外，我们发现干扰素λ通过E2-IFN-STAT3-FAS通路降低了子宫内膜对FASL介导的细胞凋亡的敏感性。本项研究探索了干扰素λ作为一种新型的参与母胎界面免疫相互作用的非冗余调节因子，有助于阐明女性自发性妊娠丢失的潜在原因。