PSGL-1蛋白O-GalNAc糖基化修饰调控单核细胞活性在动脉粥样硬化中的作用及机制研究

单核细胞在动脉粥样硬化（AS）中发挥重要作用，但发病机制未完全阐明。最新研究认为PSGL-1蛋白作为一类免疫检查点，参与免疫细胞分化调控。我们证实敲除PSGL-1基因后Apoe-/-小鼠AS病变缓解，斑块内单核细胞浸润减少、循环炎性单核细胞比例减低，提示在AS中PSGL-1蛋白参与单核细胞分化调控。O-GalNAc糖基化修饰是一种重要的蛋白翻译后修饰，参与多种生理和病理过程调控，前期研究发现AS病变人颈动脉中O-GalNAc糖基化水平升高，进一步发现单核细胞活化后PSGL-1蛋白O-GalNAc糖基化水平升高，提示PSGL-1蛋白O-GalNAc修饰在AS中发挥作用。本研究拟构建体内外AS模型，旨在研究AS因素影响单核细胞PSGL-1蛋白O-GalNAc糖基化修饰，并通过调控相关转录因子、下游靶基因表达及代谢产物变化影响单核细胞活性，并参与调控AS进展。本项目有望为AS防治提供新靶点。

Monocytes play a critical role in atherosclerosis，the pathogenesis is not fully elucidated. Recently, PSGL-1 function as a new player in the immune checkpoint landscape, which participate in the regulation of differentiation and immune functions on various immune cells. In our previous study, we have demonstrated that the Apoe-/- mice with PSGL-1 knockout developed small atherosclerotic plaques, as well as the decreased amount of DC infiltration in plaques and inflammatory monocytes in circulation, which indicated PSGL-1 play a role in regulation of monocytes in atherosclerosis. Protein O-GalNAc modification is an important post-translational modification of protein, which shows a crucial regulatory role in almost physiological and pathological processes. Our preliminary results suggested the level of O-GalNAc was increased in human carotid artery atherosclerosis; moreover, LPS significantly increased PSGL-1 O-GlcNAcylation in monocytes, suggesting the O-GalNAcylation of PSGL-1 plays an important role in AS. In the present project intends to explore that the AS factors can regulate monocytes O-GalNAcylation of PSGL-1 in vivo and in vitro, which will induce the certain transcription factors and its downstream gene expression, as well as metabolite profiles, activating monocytes and exacerbating the progress of AS, so as to affording new target for prevention and treatment of AS.