最新发现：胆固醇结晶是诱发血管慢性炎症导致动脉粥样硬化（AS）发生的危险因素，而组蛋白去乙酰化酶Sirt6介导的去脂肪酰化修饰是调控炎症重要的新机制。课题组发现：Sirt6通过去乙酰化调控AS过程中内皮炎症，但胆固醇结晶和Sirt6去脂肪酰化修饰与内皮关系不清楚。因此我们假设：Sirt6调控AS过程中胆固醇结晶诱发内皮炎症，机制与其去脂肪酰化有关。本研究运用光固化3D打印分叉血管模型，研究不同部位胆固醇结晶对内皮功能和炎症的影响；通过蛋白质修饰组学筛选Sirt6调控“差异脂肪酰化蛋白”及修饰位点，结合组学信息和AS模型，研究Sirt6对“差异脂肪酰化蛋白”和NLRP3炎性小体等作用，明确Sirt6对胆固醇结晶诱发内皮炎症的调控作用；进一步研究Sirt6是通过去脂肪酰化或去乙酰化修饰调控下游炎症因子，以及两种修饰之间关系，阐明Sirt6对内皮炎症的调控机制，为AS防治和新药研究提供实验依据。

Recent studies showed that cholesterol crystal induced chronic inflammation is a risk factor of atherosclerosis (AS). The histone deacetylase Sirtuin6 (Sirt6)-mediated defatty acylation is an important new way of regulating inflammatory response. We found that Sirt6 modulated inflammatory response by deacetylating target proteins in AS. However, the relationships between cholesterol crystal and Sirt6-mediated defatty acylation in the inflammatory response of endothelial cells during atherogenesis remain elusive. Therefore, we hypothesize that Sirt6 regulates the cholesterol crystal induced inflammatory response in endothelial cells through the defatty-acylase activity. In the present study, we investigate the effects of particular site of cholesterol crystal on endothelial function and inflammation by the Stereolithography 3D Printing of arterial bifurcation model. Furthermore, we screen the differential fatty acylation proteins and related modification sites regulated by Sirt6 through modification-specific proteomics. Then we determine the regulatory effects of Sirt6 on differential fatty acylation proteins and NLRP3 inflammasome. Further study will be performed to determine whether the regulatory effect of Sirt6 on inflammatory response is mediated by defatty acylation or deacetylation and the relationships between these deacylation in AS. The study provides the experimental and theoretical foundation for the prevention of AS and new drug development.