Septin2通过NKRF/NF-kB通路调控湍流诱导的动脉粥样硬化作用与机制研究

湍流剪切力是血管炎症、动脉粥样硬化（AS）发生的关键诱因，探究湍流剪切力诱导AS发生的机制对AS防治有重要意义。预实验发现湍流上调内皮骨架蛋白Septin2的表达；内皮特异性敲除Septin2显著缓解湍流剪切力诱导的LDLR敲低小鼠颈动脉斑块的形成；二代测序发现下调Septin2表达显著抑制NF-kB信号通路；免疫共沉淀/质谱分析表明Septin2和NF-kB抑制因子NKRF结合。我们提出假说：Septin2通过与 NKRF 竞争性结合来增强NF-kB 的转录活性，促进血管炎症和AS的发生。本课题拟利用分子、生化手段揭示Septin2/NFRF/NFKB间的新颖分子调控关系；建立湍流剪切力模型，在细胞和动物水平阐明Septin2在内皮炎症中的重要作用；结合临床样本分析明确Septin2的病理相关性。本项目将阐明Septin2在动脉粥样硬化中的作用机制，为其创新治疗提供新靶点。

Oscillatory shear stress is the key cause of vascular inflammation and atherosclerosis (AS). Exploring the mechanism of AS induced by oscillatory shear stress is of great significance to the prevention and treatment of AS. Preliminary experiments found that turbulence up-regulated the expression of the endothelial cytoskeleton protein Septin2; endothelial specific knockout of Septin2 significantly reduced the formation of carotid artery plaques in LDLR knockdown mice induced by oscillatory shear stress; second-generation sequencing found that down-regulation of Septin2 significantly inhibited NF-kB signal pathways; co-immunoprecipitation/mass spectrometry analysis showed that Septin2 binds to NF-kB inhibitor NKRF. We put forward the hypothesis that septin2 enhances the transcription activity of NF-kB by competitively binding with NKRF, thus promoting the occurrence of vascular inflammation and AS. This project intends to reveal the novel molecular regulation relationship between Septin2/NFRF/NFKB by molecular and biochemical methods; establish an oscillatory shear stress model to clarify the important role of Septin2 in endothelial inflammation at the cellular and animal levels; clarify the pathological relevance of Septin2 through clinical sample analysis. This project will clarify the mechanism of Septin2 in atherosclerosis and provide a new target for its innovative treatment.