LncRNA-PVT1基因异常甲基化的调节机制及其在子痫前期发生中的作用研究

项目名称： LncRNA-PVT1基因异常甲基化的调节机制及其在子痫前期发生中的作用研究

项目编号： No.81501276

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： 相玉倩

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 子痫前期（PE）是全世界备受重视的研究领域。大量研究显示，胎盘发育和功能受损是PE发生的关键因素，但其分子机制仍有待研究。本实验室前期发现与器官损伤和异常相关的lncRNA-PVT1基因在PE胎盘中呈显著低甲基化，且引起PVT1 lncRNA表达下调。已知PVT1与细胞增殖、迁移等功能密切相关。本项目将在临床样本、细胞系和动物模型三个层面对PE胎盘组织lncRNA-PVT1异常甲基化的调控机制及其在PE发生中的作用进行研究。检测PE胎盘lncRNA-PVT1的甲基化状态，探讨叶酸水平、甲基化相关作用酶在lncRNA-PVT1异常甲基化中的调控作用；检测PVT1 lncRNA异常表达对滋养层细胞生长和功能的影响；探讨PVT1-MYC及其他互作蛋白在PE发生中的作用机制。研究结果将为PE发生机制增加新的分子理论基础，为临床实践中降低PE的发生风险提供理论依据，为PE的临床治疗提供潜在药物靶点。

中文关键词： 子痫前期；lncRNA-PVT1；DNA甲基化；胎盘发育；动物模型

英文摘要： Pre-eclampsia (PE) have gained much attention by clinical and basic researchers worldwide. Numerous studies demonstrated that abnormal placentation was the key element in the pathogenesis of PE, however, the specific molecular mechanisms involved remain to be established. Our recent studies have discovered that the lncRNA-PVT1, related to organ injury and abnormalities, was hypomethylated in the placentas of PE. Besides, the expression level of PVT1 lncRNA induced by aberrant DNA methylation was down-regulated in the placentas of PE. Previous studies have indicated that the up-regulation of PVT1 lncRNA was related to the occurrence of metastatic tumors. In the present project, we will explore the molecular mechanism of the hypomethylation of lncRNA-PVT1 and its role in the pathogenesis of PE at three levels including the clinical samples, cell lines, and animal model. We will analyze the methylation level of genomic region neighboring the targeted CpG site in the placentas of PE; reveal the role of folic acid and DNA methylation related enzymes in regulating aberrant lncRNA-PVT1 methylation; detect the influence of aberrant PVT1 lncRNA expression on trophoblast cell growth and function; investigate the important role of PVT1-MYC and other interacting proteins in the pathogenesis of PE. The results may add new molecular mechanisms involved in the pathogenesis of PE. Furthermore, our findings may also provide theory basis for clinical controlling of PE, and provide therapeutic targets for PE.

英文关键词： pre-eclampsia;lncRNA-PVT1;DNA methylation;development of placenta;animal model