SBP1/AMPK/GSK3β通路抑制痛风发作的机制研究

痛风是常见病，尚无根治方法。我们前期：①采用iTRAQ蛋白质组学筛选并验证发现：硒结合蛋白1（SBP1）在痛风患者中表达显著低于无症状高尿酸血症（HUA）患者；②经SBP1特异抗体处理的小鼠，关节腔注射尿酸盐结晶（MSU）后引发的炎症明显重于对照；③MSU促进小鼠巨噬细胞IL-1β的释放，却抑制AMPK、GSK3β磷酸化及SBP1蛋白表达。结合最新进展：SBP1可诱导GSK3β磷酸化；AMPK/GSK3β磷酸化通路有着显著抗炎作用。故认为：SBP1不仅是痛风发病的预警因子；SBP1还可激活AMPK/GSK3β磷酸化通路抑制痛风性关节炎。为此，拟采用SBP1基因敲除和高表达小鼠验证SBP1对痛风的防治作用；利用蛋白质组学构建SBP1上下游调控网络，并验证AMPK/GSK3β通路的核心作用；最后采用体内外试验及AMPK/GSK3β抑制剂阐明SBP1防治痛风的机理，为潜在应用提供依据。

Gout is a common disease, but we still have no cure. Our previous studies: ①iTRAQ proteomics had screened and verified that selenium binding protein 1 (SBP1) decreased significantly in gout patients than in the healthy and asymptomatic hyperuricemia (HUA) patients; ②SBP1 neutralizing antibody treated mice had more severe Monosodium urate crystals (MSU)-induced-arthritis than control, this indicated SBP1 could inhibit gout; ③In vitro, we found MSU could elicit IL-1β releasing, and inhibit SBP1 expression and phosphorylation of AMPK and GSK3β. Together with the existing researches: SBP1 could induce phosphorylation of GSK3β, and AMPK/GSK3β signaling pathway had significant effects on anti-inflammation. We consider: SBP1 may indicate the prevalence of gout; SBP1 could inhibit gout through activating AMPK/GSK3β phosphorylation signaling pathway. For further investigation, SBP1 gene knock out and high-expression mice will be established to testify SBP1 protection effects on gout; proteomics methods will be used for construction of SBP1 signal network, and verification of the central role of AMPK/GSK3β pathway; in final, in vivo and in vitro experiments and AMPK/ GSK3β inhibitors will be applied for revealing the mechanisms of SBP1 in gout prevention and treatment. To provide evidences for potential future applications.