氨肽酶PSAP抑制NLRP3炎症小体活化的分子机制及其小分子干预

研究表明NLRP3炎症小体介导固有免疫反应对炎症及相关疾病的发生至关重要，但直接负调节NLRP3分子的机制尚不十分清楚。前期工作发现在多种炎症小体活化刺激下，氨肽酶PSAP可直接结合NLRP3分子，导致其不能寡聚化从而抑制炎症小体复合物的组装活化：提示PSAP可抑制NLRP3炎症小体活化。本项目拟进一步考察氨肽酶PSAP在NLRP3炎症小体活化过程中的动态变化等属性，探讨其在影响NLRP3炎症小体活化中的具体作用和环节；阐明PSAP与NLRP3相互作用的结构域，及二者相互作用对NLRP3分子结构和功能的影响；明确PSAP调节NLRP3分子功能的活性形式；借助可直接靶向PSAP的化合物及PSAP巨噬细胞敲除的小鼠，探讨PSAP介导的调节机制和痛风及肠炎等疾病的相关性及靶向PSAP的治疗学属性。本项目预期阐明NLRP3分子新的调节机制，为相关疾病的临床治疗提供药物靶标。

Studies have shown that the NLRP3 inflammasome mediates the innate immune response is essential for the development of inflammation and related diseases, but the mechanism of direct negative regulation of NLRP3 molecule is not fully understood. Previous work has found that under the stimulation of a variety of inflammasome activation, aminopeptidase PSAP can directly bind to NLRP3 molecule, leading to its inability to oligomerize and inhibit the assembly and activation of inflammasome complex: suggesting that PSAP can inhibit the activation of NLRP3 inflammasome. This project intends to further investigate the dynamic changes of PSAP during the activation process of NLRP3 inflammasome, and explore its specific role and link in influencing the activation of NLRP3 inflammasome; clarify the domain of interaction between PSAP and NLRP3, and how this interaction affect the structure and function of NLRP3; clarifies the active form of PSAP for regulating the function of NLRP3 molecule; By using the compounds that directly target PSAP and PSAP macrophage specific knockout mice and related clinical samples, aiming to explore the relationship between the PSAP-mediated regulatory mechanisms and diseases as well as the therapeutic properties for gout or colitis by targeting PSAP. This project is expected to elucidate the new regulatory mechanisms of NLRP3 molecule and provide drug targets for the clinical treatment of inflammation and related diseases.