WNT6基因在子宫内膜蜕膜化及早期妊娠丢失过程中的作用及机制研究

Early pregnancy loss is one of the primary causes responsible for reproducing failure of women during their reproductive years. Despite extensive evaluation, ~ 50% couples with a history of unexplained early recurrent pregnancy loss (UERPL) have no identifiable factors. Abnormal uterine stromal cell decidualization has been identified to have an important influence on establishing and maintaining pregnancy. Decidualization is regulated by complex molecular signaling network, but up to present time the regulation mechanism of decidualization has been remained unknown. Our previous animal researches showed that Wnt signalling pathway involved in organogenesis and embryonic development was also participated in embryonic implantation and decidualization; and uterine-specific deletion of Wnt6 in mice resulted in abnormal decidual patterning and substantial embryo loss, highlighting the concept that Wnt6 might play major roles in embryonic implantation and decidualization. However, the specific mechanism in the above regulation process has been under research. Subsequently, we found novel WNT6 missense mutation in patients with UERPL, and reported the assosiation between WNT6 gene mutation and UERPL for the first time. Based on previous results, we will explore whether WNT6 missense mutation contribute to uterine stromal cell proliferation, differentiation and apoptosis by further function research. Therefore, the objective of our study was to evaluate the role of WNT6 missense mutation and its signalling pathway in embryonic implantation and pregnancy maintenance, and provide new evidence for the etiology of UERPL.

早期妊娠丢失是育龄妇女生育失败主要原因之一，其病因复杂多样，约50%原因不明。子宫蜕膜化反应异常被认为是影响妊娠建立和维持的重要因素，蜕膜化过程受复杂的分子信号网络调控，目前对于该过程的调控机制研究仍然存在许多问题。我们前期动物研究发现参与器官形成与胚胎发育的Wnt信号通路参与了胚胎植入和蜕膜化反应调节，通路中的Wnt6基因敲除小鼠表现出子宫蜕膜发育异常、生育力下降，但其在胚胎植入和子宫蜕膜化调控过程中的具体作用机制仍处于研究阶段。在不明原因早期复发性流产患者中本课题组首次发现了WNT6基因错义突变，提示了WNT6基因突变与复发性流产的相关性。我们拟通过后续体内、体外功能实验验证WNT6错义突变是否影响子宫内膜细胞增殖、分化及凋亡，探讨WNT6基因突变及其信号通路变化对胚胎植入和妊娠维持的影响，为流产病因学研究提供证据支持。

早期妊娠丢失（early pregnancy loss，EPL）病因高度异质，临床表现复杂多样，是导致育龄女性生育失败的主要原因。本项目研究发现WNT6 c.443T>G可能不是不明原因早期复发性流产（unexplained early recurrent miscarriage，UERM）患者的致病性突变位点。基于非整倍体胚胎和异常子宫内膜容受性在EPL发生发展中的重要作用，我们继续围绕EPL中的反复胚胎种植失败（recurrent implantation failure，RIF）、早期复发性流产（early recurrent miscarriage，ERM）两大疾病类型，针对胚胎、内膜这两大重要致病因素开展基础及临床应用研究。本项目研究证实胚胎植入前遗传学检测（preimplantation genetic testing，PGT）在EPL患者中的临床应用价值，发现促性腺激素的剂量与PGT中胚胎非整倍体率及活产率无关、染色体易位对减数分裂模式的影响、PGT在易位/倒位携带者中的应用价值、移植嵌合体胚胎的临床意义、既往EPL病史与PGT助孕结局相关性等一系列成果，为EPL患者的生育风险评估和遗传咨询提供一定的临床指导。同时研究证实miR-148a-3p可能通过降调HOXC8基因抑制子宫内膜蜕膜化，从表观遗传学角度拓展RIF的病因学研究。