结核分枝杆菌胞外鞘磷脂酶Rv0888诱导肺脏中性粒细胞胞外诱捕网形成继而促进炎症反应的机制研究

结核病是由结核分枝杆菌（Mtb）引起的严重危害人类健康的一种重要传染病，以肺脏肉芽肿、纤维化和坏死等病变为特征，阐明Mtb的致病机制对于研发新型疫苗和药物均具有重要意义。前期研究表明，MtbRv0888的鞘磷脂酶活性不仅诱导小鼠肺脏产生明显的炎症反应、病理变化和中性粒细胞胞外诱捕网（NETs），而且NETs的形成与病变严重程度密切相关，推测NETs介导了小鼠肺脏的炎症反应和病理变化，但其机制不清。本项目以MtbRv0888蛋白为研究对象，以小鼠肺脏形成的NETs及其介导的炎症反应和病理变化为主线，研究Rv0888诱导NETs的形成机制，解析NETs介导小鼠肺脏炎症反应和病理损伤的信号通路，筛选消减小鼠炎症反应和病理损伤的抑制剂，阐明Rv0888诱导小鼠肺脏形成NETs介导的炎症反应机制，这不仅丰富了对Mtb致病机制的进一步理解，也为结核病新型疫苗和新药的研发奠定理论基础。

Tuberculosis (TB) is an important infectious disease and severely threatens human health which caused by Mycobacterium tuberculosis (Mtb), and characterized with the pathological lesions of lung granuloma, fibrosis and necrosis. Therefore, it is important to elucidate the pathogenic mechanism of Mtb for the development of new vaccines and drugs. Previous studies have shown that sphingomyelinase Rv0888 could not only induce obvious inflammatory reaction, pathological damage and netrophil extracellular traps (NETs) formation in lung of mice, but also there is a close connection between the formation of NETs and the severity of lesions. It is supposed that NETs mediate the inflammatory response and pathological lesions of lung in mice, but the mechanism is unknown. Our project will take Mtb Rv0888 protein as the research target and focus on the formation of NETs which mediates the inflammatory response and pathological lesions in the lung. The aims of project are to decipher the mechanism of NETs formation induced by Rv0888, analyze the signal pathways of lung inflammatory response and pathological lesions mediated by NETs in mice, confirm the inhibitors which reduce the inflammation and pathological damage in mice and elucidate the function of Rv0888 inducing NETs and inflammation of lung in mice, which could enrich the understanding of the pathogenesis of Mtb as well as provide foundation for the development of new vaccines and drugs against TB.