SIRT1介导滋养细胞早衰及其促衰老微粒形成在胎盘提前老化中的作用及机制研究

胎盘提前老化与不良妊娠结局密切相关，但其发病机制仍不清楚，临床上缺乏明确的诊断和治疗方法。我们前期实验表明，SIRT1-p53-p21信号调控体外滋养细胞正常融合和衰老；SIRT1敲除导致小鼠胎儿异常，包括胎儿生长受限和死胎，进一步基因芯片结果证实滋养细胞SIRT1缺失激活下游p53和ROCK1信号通路；此外，提前老化胎盘组织合体滋养细胞SIRT1表达下调，合体滋养微粒（STBM）脱落数量增加。本项目拟在前期研究基础上，重点从2条分子路径探讨SIRT1调控滋养细胞衰老作用于胎盘提前老化的分子机制：1）通过SIRT1-p53-p21途径诱导滋养细胞早衰；2）通过SIRT1-ROCK1诱导促衰老功能STBM形成及其脱落增加，STBM以自分泌和旁分泌方式进一步加速细胞衰老。该项目的目标是揭示SIRT1下调介导滋养细胞早衰及其促衰老STBM脱落增加加速衰老参与胎盘提前老化的作用机制。

Premature aging of placenta is implicated in a number of adverse pregnancy outcomes, including fetal growth restricition, preeclampsia, and fetal death. Understanding the underlying mechanism of this condition is therefore key in developing stragies to dignosis and treat them.Our former work confirmed silent information regulator 1(SIRT1)-p53-p21 pathway was reqiured for the cell fusion and senescence in trophoblast cells.SIRT1 knockout induced fetal growth restrction and intrauterine fetal death. Global gene expression changes were evaluated using microarray-based RNA profiling and showed the activation of p53 and ROCK1 signaling. Moreover, the premature senescece of placental tissues pesented the decressed SIRT1 expression and icreased syncytiotrophoblast microparticles (STBMs) in intervillous space. In this study, we will focuse on the role of SIRT1 on premature senescece of trophoblast cells in two ways. One is SIRT1-p53-p21 pathway in premature senescece of trophoblast cells. Another one is SIRT1-ROCK1 pathway which plays a key role in STBM shedding, and STBMs accelerat placental aging. We aim to reveal the new mechanism on SIRT1 involved in premature senescece of trophoblast cells and the formation of celluar pro-senescent microparticles for premature aging of placenta.