TET2调控滋养细胞功能及其机制研究

项目名称： TET2调控滋养细胞功能及其机制研究

项目编号： No.81501273

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李婷

作者单位： 同济大学

项目金额： 17万元

中文摘要： 滋养细胞是胎盘的基础性功能细胞，对妊娠的建立和维持具有重要作用，其功能障碍会导致多种妊娠疾病，如子痫前期等。研究表明子痫前期中存在DNA甲基化的异常调控，目前对其调控的生物学机制尚不明确。本课题组前期研究表明：与正常孕晚期胎盘相比，子痫前期胎盘中基因组DNA甲基化升高，DNA去甲基化酶TET2的转录及蛋白水平降低；在体外敲降TET2后，滋养细胞的迁移侵袭能力显著下降。这些结果提示TET2可能通过调控基因组DNA甲基化参与滋养细胞生物学功能，其异常表达可能会导致子痫前期的发生。本课题将进一步确定TET2与子痫前期的相关性；明确其参与滋养细胞的生物学功能调控；通过功能分类基因芯片、染色质免疫共沉淀等技术寻找TET2靶向调控的下游基因，明确TET2对滋养细胞生物学功能调控的作用机制；并通过小鼠模型揭示TET2对胎盘结构功能及妊娠结局的影响，为子痫前期的靶向性治疗提供新的线索和理论依据。

中文关键词： TET2；子痫前期；滋养细胞；DNA甲基化

英文摘要： Trophoblast cells, playing important roles in the establishment and maintenance of pregnancy, are basically functional to placenta. It has been reported that dysfunction of trophoblast cell can cause gestational diseases such as preeclampsia, where dysregulation of DNA methylation is always found. However, the underlying mechanism still remains elusive up to now. Our previous results showed that the level of genomic DNA methylation is increased in preeclampsia placenta in comparison to normal placenta. While the transcription and protein level of TET2 significantly reduces in preeclampsia placenta. Moreover, knockdown of TET2 obviously inhibited the migration and invasion of trophoblast cells. These results implied that TET2 regulates placenta trophoblast cell and its aberrant expression is probably one important reason for giving rise to preeclampsia. Thus, on the basis of the comprehensive study, this project is helpful to understand TET2 biological functions in placenta trophoblast cell and its critical roles in the progression of preeclampsia, identify the downstream key functional genes by microarray, CHIP-seq, etc, reveal the effect of TET2 on placental structure and pregnancy outcome through the mouse model, thereby providing new strategies and evidences for target therapy of preeclampsia.

英文关键词： TET2;preeclampsia;trophoblast cells;DNA methylation