KDM5C调控胎盘滋养层细胞侵袭和增殖的机制研究

母-胎界面滋养层细胞增殖与侵袭能力异常是导致妊娠相关疾病的主要原因，但其调控机制尚未阐明。我们前期研究发现在妊娠失败绒毛样本中组蛋白去甲基化酶KDM5C表达异常，其高表达与复发性流产、子痫前期和胎儿生长受限等产科综合征密切相关，而低表达在胎盘植入和滋养细胞肿瘤等病理状态下被发现。依据前期DNA-蛋白质互作测序实验（CUT&Tag）的结果，我们发现KDM5C对滋养层细胞侵袭和增殖的重要基因TGFβ2、RAGE等具有调控作用，提示KDM5C可能的妊娠维持机制。本项目将在上述研究基础上，进一步应用人类滋养细胞干细胞、绒毛外植体和滋养层细胞类器官培养技术，利用疾病小鼠模型，通过染色质免疫共沉淀、微流控侵袭监测和基因rescue等研究策略，阐明KDM5C调控滋养层细胞增殖与侵袭的机制，为临床妊娠相关疾病的诊治和防控提供科学依据。

Abnormal proliferation and invasion of trophoblastic cells at the maternal-fetal interface is one of the main causes of pregnancy-related diseases, but its regulatory mechanism has not yet been fully elucidated. In the preliminary study, we found that abnormal expression of the histone demethylase KDM5C in the villi samples of patients with pregnancy failure. Its high expression was closely related to recurrent abortion, preeclampsia, fetal growth restriction and other major obstetric syndromes, while its low expression was found in pathological states such as placenta implantation and trophoblastic tumors. According to the results of our DNA-protein interaction sequencing methods (CUT&Tag), we firstly verify the regulatory role of KDM5C on the key genes of TGFβ2 and RAGE, which regulate trophoblast invasion and proliferation, suggesting that KDM5C plays an important role in pregnancy maintenance. This project will base on the above research, proposed further application in human trophoblastic stem cells, human villous explant culture, trophoblastic organoids and disease mice model, through chromatin immunoprecipitation, microfluidic-based invasion assays and gene rescue strategies. Together, we confirmed on the molecular mechanism of KDM5C in regulation trophoblast invasion and proliferation to provide scientific basis for the diagnosis, treatment and prevention of pregnancy-related diseases.