HDAC1/7低表达介导的组蛋白乙酰化修饰异常在蜕膜基质细胞过度衰老致反复妊娠丢失中的机制研究

蜕膜化的正常建立是维持成功妊娠的关键。最新研究提示细胞衰老在蜕膜化过程中发挥关键作用，衰老的炎症分泌表型有利于蜕膜化的进展，但蜕膜化过程中细胞衰老的精细调控以及与妊娠相关疾病发生的关系仍有待深入阐释。我们前期利用10×单细胞转录组测序技术，发现反复妊娠丢失患者的蜕膜基质细胞呈现过度衰老状态，组蛋白去乙酰化酶HDAC1/7异常表达。基于最新文献报道和课题组前期研究结果，我们提出科学假设：反复妊娠丢失患者内膜基质细胞HDACs表达异常引起组蛋白乙酰化修饰改变，由此导致的蜕膜基质细胞过度衰老是诱发反复妊娠丢失发生的关键原因之一。因此本项目拟聚焦蜕膜衰老这一新的研究领域，结合前期10×单细胞转录组测序数据，利用CUT&Tag测序、组织芯片和体内体外模型等深入研究蜕膜衰老的特征，揭示组蛋白乙酰化修饰在反复妊娠丢失患者蜕膜基质细胞过度衰老中的作用，为反复妊娠丢失防治提供新的干预途径和靶点。

Decidualization of the endometrium is essential for successful implantation and pregnancy. Recent research suggests that cellular senescence plays a key role in decidualization. The inflammatory secretion phenotype of cellular senescence is conducive to the progress of decidualization, but the fine regulatory mechanisms of decidual senescence and its effect on pregnancy-related diseases remain unknown. Based on previous and our preliminary studies, we speculated that abnormal histone acetylation induced excessive decidual senescence, resulting in the occurrence of recurrent pregnancy loss(RPL). In current investigation, combining our previous 10× single-cell sequencing data, we will employ a clinical cohort study of RPL, uterine conditional knockout mouse model, as well as in vitro model of decidualization using CUT & Tag sequencing, tissue chips to investigate the characteristics of decidual senescence in RPL and reveal the role of histone acetylation modification in the decidual senescence. It is hoped that a better understanding on mechanisms of decidual senescence will help us to reveal the pathological causes of RPL.