LRF介导的内质网应激在胚胎着床过程中的作用及其调节机制

Embryo implantation is a critical step for the successful pregnancy. To date, although many specific factors have been identified during the implantation period, the exact molecular mechanism of embryo implantation is still unknown. Thus, it is a major target to reveal the regulation mechanism of embryo implantation for the reproductive biology. Endoplasmic reticulum stress plays an important role in mammalian reproductive process,and previous studies in our laboratory revealed a possible relationship between endoplasmic reticulum stress and embryo implantation. LRF is a novel leucine zipper protein transcription factor involved in the endoplasmic reticulum stress pathway, and the lower litter size of the LRF-/- female mice indicated that LRF might play an important role in mouse embryo implantation. The purpose of this study was to further investigate the spatiotemporal expression and regulation of LRF mRNA and protein in the mouse uterus during embryo implantation using LRF knockout mouse and related animal models.The effect of LRF in endometrial receptivity and decidualization during early pregnancy was also been detected. Meanwhile, the SSH, biochip, promoter analysis and co-immunoprecipitation techniques were used to confirm the molecular mechanism of LRF-mediated endoplasmic reticulum stress during embryo implantation.Our results would provide a new research direction for further investigation of the mechanisms regulating embryo implantation,and reveal a new pathway responsible for the improvement of animal reproductive rate and the ability to treat infertility.

胚胎着床是妊娠成功的关键环节，这一复杂的生殖过程涉及诸多因子的参与和协同作用，揭示其机制一直是生殖生物学的重点之一。内质网应激作为参与机体多种细胞反应的调节机制在生殖过程中发挥着重要的作用。LRF是新发现的参与机体内质网应激调节的碱性亮氨酸拉链蛋白转录因子。前期研究发现，内质网应激参与胚胎着床的调控；LRF-/-雌鼠的窝产仔数显著降低，LRF可能与小鼠胚胎着床过程密切相关。本项目拟通过敲除小鼠等多种动物模型，进一步研究LRF在小鼠胚胎着床期子宫中的表达与调节，深入分析LRF对小鼠子宫内膜容受性和蜕膜化的影响，并利用SSH、生物芯片、启动子分析、免疫共沉淀等技术，揭示LRF介导的内质网应激相关信号通路在小鼠胚胎着床过程中的作用机制，为进一步阐明胚胎着床的分子机理、提高动物繁殖率及不孕症的治疗等提供新思路和理论依据。

胚胎着床是妊娠成功的关键环节，这一复杂的生殖过程涉及母胎双方诸多因子的参与和协同作用。充分认识胚胎着床的机制对于解读生殖领域面临的诸多难题，如不孕不育、流产、提高体外授精-胚胎移植（IVF-ET）成功率、动物繁殖率以及新型避孕药物的研制等均具有十分重要的意义。该项目证实内质网应激反应参与了卵泡发育、凋亡调节。利用多种体内小鼠模型和体外细胞模型阐明了LRF在小鼠早期妊娠子宫中的时空表达与分布，明确了雌、孕激素对LRF的调控效应。确定LRF对小鼠子宫内膜容受性和蜕膜化的影响，证明LRF通过影响子宫上皮细胞蜕膜化参与胚胎植入的调控。揭示了ERS与胚胎着床的关系，从新的视觉阐明了胚胎着床的网络调控机制，为全面认识胚胎着床的分子机理、提高动物繁殖率及不孕症的治疗等提供了新思路和理论依据。该项目共发表SCI收录研究论文17篇，培养博士研究生3名，硕士研究生5名。