FGFR1的蛋白翻译后SUMO化修饰对动脉粥样硬化血管内皮病理性表型转换的调控与机制研究

Atherosclerosis is one of the typical vascular remodeling diseases, in which the vascular inflammation mediated by pathological endothelial phenotypic switch is a major biological event in charge of vascular homeostasis imbalance and remodeling. However, the correlated regulatory mechanism in this process is largely unknown. Our previous study uncovered the critical role of FGFR1 in endothelial-mesenchymal transition in atherosclerosis. On the other hand, others and our previous work demonstrated that post-translational SUMO modification played an important role in vascular remodeling diseases, such as arteriosclerosis and pathological angiogenesis. In the pilot study for the current proposal, we identified the endogenous SUMOylation of FGFR1 in vascular endothelial cell. Negative regulation of endothelial FGFR1 SUMOylation was evidenced in pro-inflammatory cytokines induced endothelial-mesenchymal transition in vitro and atherosclerosis development in mice. Therefore, the current proposal aims to investigate the role of endothelial FGFR1 SUMOylation in the atherosclerosis progression, and to elucidate the cellular and molecular mechanisms of FGFR1 SUMOylation in regulating endothelial phenotypic switch and vascular inflammation in atherosclerosis. The accomplishment of this study will help to understand the pathogenesis of atherosclerosis and correlated cardiovascular diseases from a new perspective, and provide a novel theoretical basis and new strategies for the intervention and treatment of human cardiovascular diseases.

动脉粥样硬化是典型的血管重构疾病，其中内皮病理性表型转换介导的血管炎症是导致血管稳态失衡和重构的核心生物学事件之一，然而相关调控机制知之甚少。我们以往参与的工作揭示了FGFR1在调控动脉粥样硬化内皮-间充质转换中的关键作用。而我们以及其他团队之前的工作揭示了蛋白翻译后SUMO化修饰在动脉硬化和病理性血管生成等血管重构疾病中有着重要地位。本项目的前期工作中，我们发现血管内皮存在内源性FGFR1的SUMO化修饰，初步明确其对炎症因子诱导的内皮-间充质转换和小鼠动脉粥样硬化的负调控作用。因此，本项目拟运用经典的生物医学研究手段结合计算生物学、ChIP-seq等系统性分析方法，研究FGFR1的SUMO化修饰在动脉粥样硬化中的病理作用，及其调控疾病过程中血管内皮表型病理性转换与血管炎症的生物学机制，从蛋白翻译后的新角度揭示动脉粥样硬化致病机理，为相关心血管疾病的诊断治疗提供新的重要靶点以及理论基础。