基于母胎界面-骨髓间HIFs-STAT3-PR信号环路与MDSCs交互作用研究补肾安胎方改善着床微环境的机制

基于前期（编号：81473494，30873347）基础：补肾安胎方能改善着床微环境、协调VEGF等着床相关因子的表达，促进胎盘血管形成，提高模型小鼠着床率；结合新近发现：着床早期，骨髓、母胎界面中缺氧诱导因子（HIF）、孕激素受体（PR）相辅相成，调控STAT3表达，促进髓系衍生抑制性细胞（MDSCs）活化、聚集，以利于胚胎免疫豁免及胎盘血管形成；体现了局部与整体的关系，及“肾主骨生髓、肾主生殖”的重要意义。故提出假说：补肾安胎方通过HIFs -STAT3- PR信号环路调控母胎界面相关因子及MDSCs功能；补肾、活血组分各有侧重，协同作用，调节母胎耐受，促进胚胎着床。本项目拟以复发性流产（RSA）模型为研究对象，通过在体与体外实验，动态观察胚胎着床率、MDSCs亚型及活性、胎盘血管形成，从整体、组织、细胞和分子水平，系统阐述补肾安胎方改善胚胎丢失的机制，为临床运用提供坚实的实验依据。

In previous study (NO.81473494, NO.30873347), we have found that Bushen Antai recipe could improve the microenvironment of maternal-fetal interface as well as modulate the expression of angiogenesis factors such as VEGF, thus promoting the development of vascular network and implantation rate of mice in the model group. Recent studies have investigated that the HIF signal and PR signal in the bone marrow and maternal-fetal interface could complement each other during early pregnancy, to regulate the expression of STAT3 and promote the activation and aggregation of myeloid-derived suppressor cells (MDSCs), which facilitate the immune tolerance of embryos and the formation of blood vessels in placenta. This process reflects the relationship between whole and parts and embodies that the kidney dominates bone, manufactures marrow as well as governs reproduction. Therefore, we propose the hypothesis that Bushen Antai recipe could promote the expression of related factors in the maternal-fetal interface and MDSCs function through regulating PR-STAT3-HIFs signal loop. Moreover, The components of tonifying kidney and activating blood have their respective emphases, which would play a synergistic role in regulating maternal-fetal immune tolerance and improving pregnancy outcomes. The RSA mice model will be used as the research objects. Furthermore, It will be applied with dynamically observation of embryo implantation rate, placental angiogenesis, MDSCs subtypes and activity through in vivo and in vitro experiments. Taken together, from the perspectives of the whole, tissue, cell and molecular levels, we hope to systematically elaborate the mechanisms of Bushen Antai recipe in improving pregnancy outcomes, thus providing the reliable experimental basis for clinical applications.