组蛋白去乙酰化酶Sirt1/Sirt6在动脉粥样硬化内皮炎症反应的作用及机制研究

项目名称： 组蛋白去乙酰化酶Sirt1/Sirt6在动脉粥样硬化内皮炎症反应的作用及机制研究

项目编号： No.81470549

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： 林蓉

作者单位： 西安交通大学

项目金额： 73万元

中文摘要： 新近报道：Sirtuins蛋白家族成员Sirt1和Sirt6协同参与动脉粥样硬化（AS）的发生。课题组发现：Sirt1通过去乙酰化NF-κB调控AS中内皮炎症因子CD40等，但Sirt6对内皮炎症因子的作用和机制以及与Sirt1关系仍不清楚。因此我们假设：Sirt6通过去乙酰化作用调节AS中内皮炎症反应并与Sirt1有关。本研究运用基因芯片技术筛选Sirt6调控的差异基因；结合筛选信息和AS模型，探讨Sirt6对筛选的差异基因和炎症因子CD40、CRP作用，揭示AS过程中Sirt6对内皮炎症的调节作用；进而研究Sirt6对核转录因子NF-κB、FoxOs等影响，阐明其机制是直接通过核转录因子NF-κB等去乙酰化修饰，还是通过其靶基因启动子区的组蛋白H3去乙酰化发挥作用；再通过Sirt6与Sirt1关系研究，明确Sirt6对内皮炎症的作用是否受Sirt1调节，为AS防治提供新药物靶点和策略。

中文关键词： 组蛋白去乙酰化酶Sirt1；组蛋白去乙酰化酶Sirt6；动脉粥样硬化；血管内皮细胞；炎症反应

英文摘要： Recent studies indicated that the synergism of Sirt1 and Sirt6, members of sirtuins family, is closely related to the pathogenesis of atherosclerosis (AS). Our previous studies found that Sirt1 regulated vascular endothelial inflammation by deacetylating NF-κB in AS. However, the underlying molecular mechanisms of Sirt6 in the regulation of vascular endothelial inflammation in AS and its relationship with Sirt1 are unclear. Therefore, we hypothesize that Sirt6 regulates vascular endothelial inflammation by deacetylating its target proteins in AS, and the mechanism is related to Sirt1. The inflammatory related targets of Sirt6 in AS are derived from the determination using the GeneChip technology. The effects of Sirt6 on inflammatory factors CD40, CRP and nuclear factors NF-κB, FoxOs are determined in vivo and in vitro. Further, we study whether Sirt6 regulate inflammation directly or not by deacetylating NF-κB. And Sirt6 related acetylation sites on histone H3 will also be clarified. Finally, we performed to elucidate the relationship between Sirt6 and Sirt1. The study provides new drug targets and theoretical bases in AS.

英文关键词： sirtuin 1;sirtuin 6;atherosclerosis;vascular endothelial cell;inflammation