脓毒症是烧、创伤外科及危重病医学面临的难题之一，巨噬细胞过度活化是其发生、发展的根本环节，而Notch信号通路与巨噬细胞的极化、炎症因子释放密切相关。项目组前期实验结果显示：烧伤脓毒症发生时，巨噬细胞内Notch信号通路处于过度活化状态，SIRT1的表达受到明显抑制。给予SIRT1激动剂可显著降低烧伤脓毒症小鼠的死亡率及过度炎症反应，抑制Notch信号通路活化，明显改善脏器损伤。然而，烧伤脓毒症时SIRT1在巨噬细胞中的具体调控机制，及其与Notch信号通路的调控应答机理尚不明确。据此，本研究拟在前期研究基础上，从调节巨噬细胞的功能着手，通过基因敲除，定点突变等分子生物学方法，探讨SIRT1/Notch调控应答对巨噬细胞状态及功能的影响，并重点阐述脓毒症时巨噬细胞中SIRT1/Notch信号通路的调控应答机制，为减轻失控性炎症反应，提高脓毒症的生存率提供新的理论基础及治疗靶点。

Sepsis is a challenging problem in critical care medicine research. Excessive activation of macrophages is the key link in the development and progression of sepsis. Notch pathway is closely related to the polarization of macrophages and the release of inflammatory cytokines. Previous study has showed that Notch pathway in macrophages was over activated while the expression of SIRT1 was significantly suppressed during sepsis after burns. SIRT1 agonist could remarkably reduce the mortality of mice suffered from sepsis after burns and degrade the excessive inflammatory reaction. Meanwhile, the activation of Notch pathway was significantly suppressed and the viscera function was improved. However, the mechanism of SIRT regulation in macrophages in sepsis is still unclear. Accordingly, based on the previous research, we are planning to explore the interaction of SIRT1-Notch pathway in regulate the function and state of macrophages in sepsis through gene knockout and molecular biology methods. It is critical to clarify the SIRT1-Notch pathway interaction in macrophages. The study is expected to provide new theoretical basis and therapeutic targets to reduce uncontrolled inflammation and improve the survival rates in sepsis.