钙调蛋白复合物ANXA1-S100A11调控胚胎着床和妊娠维持的分子机制研究

Endometrial receptivity, and subsequently the transition of endometrium to decidua are the prerequisite for successful pregnancy. Our previous study indicated that calmodulins, S100A11 and ANXA1 down-regulated in endometrium and decidua of early pregnancy loss patients, respectively, which indicates ANXA1 and S100A11 may be critical to the process of embryo implantation and pregnancy maintenance. Furthermore, we found that ANXA1 regulated translocation of S100A11 from nucleus to cytoplasm by interacting with S100A11 in endometrium, and also the complex of ANXA1-S100A11 mediated Ca2+ influx and release in endoplasmic reticulum (ER) Ca2+ store. Accordingly, in this project we will identify the location and interaction of ANXA1-S100A11 in clinic samples from endometrium and decidua with early pregnancy loss, respectively, and, explore the roles of ANXA1-S100A11 complex on endometrium receptivity, decidulization and pregnancy maintenance in vivo and in vitro. Taken together, this project will not only disclose the contributions of calcium and ANXA1-S100A11 complex to the critical physiological processes of early pregnancy including embryo implantation, decidulization and pregnancy maintenance, but also elucidate the new pathological molecular mechanisms of recurrent embryo implantation and early pregnancy.

胚胎着床决定妊娠结局。着床失败或基质细胞蜕膜化异常是妊娠失败的主要原因，但其机制不清。我们前期研究发现反复种植失败子宫内膜和复发性流产蜕膜组织中钙调蛋白S100A11和ANXA1表达均显著降低,提示钙调节机制在胚胎着床和妊娠维持过程中发挥重要作用；进一步研究发现子宫内膜S100A11与ANXA1形成复合物,在EGF调节下发生核浆转位,参与调控内质网钙库中钙离子摄取和释放。本项目将在上述研究基础上，利用CO-IP和共聚焦显微镜等技术观察该复合物功能体异常与反复着床失败、复发性流产之间的关联机制;利用CRISPR/Cas9敲除或过表达细胞模型,探讨该复合物在子宫内膜容受、基质-蜕膜化和蜕膜化维持中的分子机制;利用基因敲除动物模型,明确该复合物对胚胎植入及妊娠维持的时序性作用及其机制。通过本项目研究，不仅能系统探究早期妊娠发生新机制，同时为着床失败及早期妊娠丢失病人的临床诊治工作提供新思路。

胚胎着床决定妊娠结局。着床失败或基质细胞蜕膜化异常是妊娠失败的主要原因，但其机制不清。我们前期研究发现反复种植失败子宫内膜和复发性流产蜕膜组织中钙调蛋白S100A11和ANXA1表达均显著降低,提示钙调节机制在胚胎着床和妊娠维持过程中发挥重要作用；进一步研究发现子宫内膜S100A11与ANXA1形成复合物,在EGF调节下发生核浆转位,参与调控内质网钙库中钙离子摄取和释放。本项目将在上述研究基础上，利用CO-IP和共聚焦显微镜等技术观察该复合物功能体异常与反复着床失败、复发性流产之间的关联机制;利用CRISPR/Cas9敲除或过表达细胞模型,探讨该复合物在子宫内膜容受的分子机制;利用基因敲除动物模型,明确该复合物对胚胎植入及妊娠维持的时序性作用及其机制。通过本项目研究，不仅能系统探究早期妊娠发生新机制，同时为着床失败及早期妊娠丢失病人的临床诊治工作提供新思路。