IRF9对动脉粥样硬化的作用及其机制研究

Atherosclerosis is the common cause of coronary artery disease and stroke also is the primary cause of cardiovascular events which lead deaths. It is well known that atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. Macrophage foam cells play a critical role in the occurrence and development of atherosclerosis. The generation of these cells is associated with imbalance of cholesterol influx, esterification and efflux. Interferon regulatory factor 9 (IRF9) belongs to the IRF family and participates in a series of molecular pathways relating to cell proliferation, oncogenesis, apoptosis and innate immunity. Recently study proved that IRF9 has a critical role in cardiovascular diseases and metabolic diseases. Considering the important location of IRF9 in the innate immune network and the intimate connection between immune response and cardiometabolic disease, we questioned whether IRF9 can influence the pathogenesis of pathological atherosclerotic conditions. In this project, we will use LDLR and IRF9 double knockout mice as model to investigate the effect of IRF9 in atherosclerosis and illustrate the underling molecular mechanisms.

动脉粥样硬化是一种脂质过度沉积在动脉血管壁的慢性炎症性疾病。巨噬细胞泡沫化参与了动脉粥样硬化斑块的起始、发展和破裂的全过程。巨噬细胞内的胆固醇代谢是其泡沫化的关键环节。干扰素调节因子9(Interferon regulatory factor 9 ，IRF9)，属于IRF家族转录因子的一员，参于了细胞增殖、肿瘤形成、细胞凋亡和天然免疫的信号通路。本项目组前期研究发现IRF9在心血管疾病和代谢性疾病中具有重要作用。由于IRF9在天然免疫以及心血管、代谢性疾病中具有重要地位，本项目拟探讨IRF9对动脉粥样硬化病理过程的作用。本项目拟运用LDLR和IRF9双基因敲除小鼠，构建动脉动脉粥样硬化模型，研究IRF9对动脉粥样硬化的作用，并运用细胞生物学和分子生物学技术，探讨IRF9对巨噬细胞泡沫化的调控作用，探讨其分子机制。本项目拓展了IRF9基因功能的研究，并为探索动脉粥样硬化的新靶点提供理论依据。

动脉粥样硬化是一种脂质过度沉积在动脉血管壁的慢性炎症性疾病。巨噬细胞泡沫化参与了动脉粥样硬化斑块的起始、发展和破裂的全过程。巨噬细胞内的胆固醇代谢是其泡沫化的关键环节。干扰素调节因子9(Interferon regulatory factor 9 ，IRF9)，属于IRF家族转录因子的一员，参于了细胞增殖、肿瘤形成、细胞凋亡和天然免疫的信号通路。本项目组前期研究发现IRF9在心血管疾病和代谢性疾病中具有重要作用。由于IRF9在天然免疫以及心血管、代谢性疾病中具有重要地位，本项目研究IRF9对动脉粥样硬化病理过程的作用。本项目运用LDLR和IRF9双基因敲除小鼠，构建动脉动脉粥样硬化模型，发现IRF9基因敲除促进动脉粥样硬化斑块形成，通过骨髓移植模型验证了IRF9通过对骨髓来源的巨噬细胞影响动脉粥样硬化斑块的形成，并通过体外培养巨噬细胞发现IRF9对巨噬细胞泡沫化和黏附功能的调控作用。本课题组发现了IRF9在动脉粥样硬化的病理机制中发挥重要作用，为动脉粥样硬化的防治靶点探索理论依据。