Plekhs1在子宫接受态转变及胚胎着床过程中的作用研究

Embryo implantation is a process in which the embryo and uterus establish tight physiological and physical relationship to support the embryo further development in the uterus and culminate in parturition. For successful implantation, the development of synchronized preimplantation embryo to the blastocyst stage, differentiation of uterus to receptive state, and reciprocal cross-talk between the blastocyst and uterus are very essential. Although in vitro fertilization and embryo-transfer techniques have already been advanced, implantation rates remains to be disappointingly low, probably due to the embryos being transferred into a non-receptive uterus. Thus it is of importance to discover more effective molecular markers and unravel the molecular mechanism of uterine receptivity. Plekhs1 is a PH-domain containing molecule and its biological functions are unknown. Our preliminary data indicated that plekhs1 is not directly regulated by ovarian hormone, but highly correlated with uterine receptivity during embryo implantation. The aim of this project is to investigate the expression, regulation, function and molecular mechanism of plekhs1 during uterine receptivity transition and embryo implantation by using various animal models, molecular methods and genome editing techniques.

胚胎着床是胚胎和母体子宫建立紧密的生理和物理联系的过程，是胚胎在母体子宫中进一步发育，直至分娩的基础。胚胎发育到激活的囊胚、子宫同步分化至接受态、以及胚胎和子宫之间的“相互对话”是成功的胚胎着床所必须的。目前，尽管体外受精和胚胎转移技术已经相对成熟，但在人类辅助生育过程中，由于子宫接受态的问题，移植胚胎的着床率仅 20%左右。因此，发现有效的子宫接受态标志分子和深入认识子宫接受态的机理，对于胚胎着床而言具有重要的理论意义和现实需求。Plekhs1是含PH结构域的分子，其生物学功能未知。我们的初步研究表明，Plekhs1是一个不受卵巢激素调节的，与子宫接受态转变高度相关的标志分子。本项目拟利用多种动物模型、分子生物学手段及基因组编辑技术研究Plekhs1在子宫接受态转变和胚胎着床过程中的表达、调节及功能，以及其发挥作用的分子机理。

子宫接受态建立是胚胎着床的关键。利用多种动物模型结合分子生物学手段，本研究发现plekhs1分子与子宫接受态建立紧密相，Msx1/2可能是其上游调节分子。利用表达plekhs1 shRNA的AAV2腺相关病毒（AAV2-plekhs1-shRNA）体内体外实验发现，敲低plekhs1影响胚胎着床与妊娠结局。本研究还进一步建立了plekhs1基因敲除鼠，以及plekhs1-iCre小鼠子宫上皮特异性表达Cre工具鼠，为进一步的研究奠定基础。