组蛋白乙酰化修饰的SRC-3调控JAK/STAT信号通路在子痫前期发病中的机制研究

Reduction of trophoblast invasion leads to placenta’s shallow implantation, and this is a key to the pathogenesis of preeclampsia. On the basis of preliminary work, the project proposes to apply many kinds of cell molecular biology and epigenetics technologies, through the cell - villi explant - animal model, from in vitro to in vivo, binding deacetylation enzyme and pathway inhibitors, which aims to explore the role of epigenetic modification (histone acetylation) of SRC-3 in the process of pregnancy and the correlation of biology function relating to trophoblast and endothelial cell. Using anoxia/reoxygenation conditions in vitro model to mimic the mechanism of preeclampsia, the project reveals the oxidative stress theory of preeclampsia in "two stage" mode. By detecting the activation level of JAK/STAT signaling pathway in the process of placenta implantation and vascular recasting, our purpose is to find that SRC-3 recruits acetylation enzyme p300 /CBP to conduct histone acetylation modification, then mediates JAK/STAT signaling pathway in pregnancy and preeclampsia. Besides, from the perspective of epigenetics, this study hopes to explore the specific markers of preeclampsia and to provide adequate theoretical basis for its etiology and mechanism. In addition, we hope to provide solid foundations for the diagnosis, prevention and clinical experiments about drug application of preeclampsia.

滋养细胞侵袭力降低导致胎盘浅着床是子痫前期发病的关键原因。本项目在前期工作基础上，拟采用细胞分子生物学及表观遗传学技术，通过细胞—绒毛外植体—动物模型系列路径实现从体外到体内的深入研究，结合去乙酰化酶抑制剂和通路特异性抑制剂等干扰因素，多角度、多层面探讨妊娠过程中SRC-3的表观遗传学修饰（组蛋白乙酰化）与滋养细胞及内皮细胞生物学功能的相关性。利用缺氧/复氧条件构建子痫前期体外模型，循序渐进地验证氧化应激损伤在子痫前期病因学说“二阶段”模式中的关键作用。检测与“胎盘着床”、“血管重铸”过程密切相关的JAK/STAT信号通路的活化水平，明确SRC-3招募乙酰化酶p300/CBP进行组蛋白乙酰化修饰，介导JAK/STAT信号通路在妊娠及子痫前期发病中的机制。期望本研究能够从表观遗传学的角度，为探寻子痫前期的特异性标记物和病因提供理论依据，此外，为子痫前期的诊断、防治和临床药物的应用奠定基础。

滋养细胞侵袭力降低导致胎盘浅着床是子痫前期发病的关键原因。本项目在前期工作基础上，采用细胞分子生物学及细胞生物学技术，结合氧化应激模型和通路特异性抑制剂等干预方式，全面探讨妊娠过程中SRC-3与滋养细胞及内皮细胞生物学功能的相关性。通过检测与“胎盘着床”、“血管重铸”过程密切相关的AKT/mTOR信号通路的活化水平，我们的研究证实，SRC-3在PE胎盘组织中的表达明显下降，氧化应激损伤通过SRC-3/AKT/mTOR信号通路影响滋养细胞及血管内皮细胞的生物学功能。该项目充分阐述了氧化应激损伤及SRC-3/AKT/mTOR信号轴在妊娠及子痫前期发病中的具有重要的作用。