犬尿喹啉酸对NLRP3炎症小体活化及相关炎症疾病的调控作用与机制研究

NLRP3炎症小体异常活化导致多种炎症疾病，因此其成为炎症疾病防治的潜在靶点，但其活化调控机制仍不甚清楚。我们前期研究发现，色氨酸代谢产物犬尿喹啉酸（Kynurenic acid，KYNA）可抑制NLRP3炎症小体活化并减轻LPS诱导的系统性炎症，其机制与KYNA激活GPR35/β-arrestin-2信号通路密切相关。据此我们推测：KYNA通过GPR35抑制NLRP3炎症小体活化并改善相关炎症疾病。本课题将通过体外实验验证KYNA对NLRP3炎症小体活化的抑制作用，并阐明KYNA通过激活GPR35/β-arrestin-2信号通路抑制NLRP3炎症小体活化的分子机制，最后通过体内实验确定KYNA对NLRP3炎症小体相关炎症疾病的治疗作用。本课题将进一步阐明调控NLRP3炎症小体活化的新机制，并为NLRP3炎症小体相关炎症疾病的防治提供新靶点。

Aberrant activation of NLRP3 inflammasome leads to various inflammatory diseases, therefore it becomes a potential target for the prevention and treatment of inflammatory diseases. However, the regulatory mechanism of NLRP3 inflammsome activation is still not clear. Our previous studies showed that Kynurenic acid (KYNA), a metabolite of tryptophan, could inhibit NLRP3 activation and attenuate LPS-induced systemic inflammation, which was closely related to the GPR35/β-arrestin-2 signaling pathway activated by KYNA. According to this, we suggest that KYNA inhibits the activation of NLRP3 inflammasome via GPR35 and improves NLRP3 inflammasome-related inflammatory diseases. In this study, we aim to investigate the inhibitory effect of KYNA on the activation of NLRP3 inflammasome, and to elucidate the molecular mechanisms of KYNA against NLRP3 inflammasome by activating GPR35/β-arrestin-2 signaling pathway through in vitro experiments, and finally to determine the therapeutic effect of KYNA on NLRP3 inflammasome-related inflammatory diseases through in vivo experiments. This project will further elucidate the new regulatory mechanisms of the activation of NLRP3 inflammasome and provide new targets for the prevention and treatment of NLRP3 inflammasome-related inflammatory diseases.