MeCP2在增龄性EPCs功能障碍中的作用及机制

项目名称： MeCP2在增龄性EPCs功能障碍中的作用及机制

项目编号： No.81471399

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈书艳

作者单位： 上海交通大学

项目金额： 70万元

中文摘要： MeCP2是广泛表达于机体各组织细胞的一种转录抑制因子，在许多病理情况下存在MeCP2的表达失调。迄今MeCP2对EPCs的调控作用尚不清楚。我们前期研究结果表明：SIRT1对EPCs功能具有正向调控作用，衰老EPCs中MeCP2的表达水平升高而SIRT1水平下降。因此我们提出MeCP2可能通过抑制SIRT1表达影响EPCs功能的假设。为验证这一假设，我们将通过人EPCs、大鼠衰老模型和小鼠动脉粥样硬化模型，采用染色质免疫共沉淀、定量PCR、RNA干扰、基因过表达、Westernblot等手段，从分子、细胞、动物整体水平多方面明确MeCP2在衰老EPCs功能障碍中的作用，证实MeCP2通过抑制SIRT1表达影响EPCs功能，并进一步探讨MeCP2对SIRT1的调控机制。本项目将从MeCP2这个新视点为揭示增龄性EPCs功能障碍的机制奠定基础，为动脉粥样硬化性疾病的防治提供新的思路。

中文关键词： 动脉粥样硬化；内皮祖细胞；衰老

英文摘要： Methyl-CpG-binding protein 2 (MeCP2), a methylation dependent transcriptional repressor, is widely expressed in various organic tissues and cell types. MeCP2 is deregulated in many pathological conditions. To date, however, a role for MeCP2 that plays in the regulation of endothelial progenitor cells (EPCs) function has been completely unknown. Previous study from our group have shown that the expression level of MeCP2 is markedly increased, whereas the level of SIRT1, which has positive effects on EPCs function is decreased in senescent EPCs. Therefore, we postulate that MeCP2 may impair EPCs function via transcriptional repression of SIRT1. To test this hypothesis, experimental techniques such as Chromatin Immunoprecipitation, Real-time quantitative PCR, adenoviral mediated gene overexpression and RNA interference are to be used. By virtue of using human endothelial progenitor cells, model of aging rats and ApoE-/- mice atherosclerotic animal model, we aimed to determine the role for MeCP2 in dysfunction of senescent EPCs, to confirm MeCP2 induced EPCs dysfunction via repression of SIRT expression, and to further explore the mechanism(s) of SIRT1 regulation by MeCP2, from molecular, cellular to whole animal level. The present study may help lay a foundation for revealing the mechanisms of ageing EPCs dysfunction from the new viewpoint of MeCP2 and may also provide a new concept for the prevention and treatment of arterial atherosclerotic diseases.

英文关键词： arterial atherosclerosis;endothelial progenitor cells;senecence