Abstract:The imbalance of Th17/Treg is of great significance to the pathogenesis of rheumatoid arthritis(RA),but the causes of the imbalance are still unclear. Leptin contribute to the pathologic process of RA, and obesity can increase leptin level and exacerbated RA inflammation, which is closely related to the disease activity of RA. In vitro studies have suggested leptin could promote Th17 while inhibit Treg, however, its mechanism, the in vivo effect and its relationship to obesity-associated arthritis are still uncertainty. Based on our pervious study, we hypothesis that leptin may cause Th17/Tregs imbalance via mTOR-SOCS-STAT pathway. We will carry out the following studies: Firstly, CD4+CD25+ Treg and CD4+CD25-Teff will be sorted to explore molecular mechanism by which leptin regulate Th17/Treg balance, secondly, obesity-associated arthritis model and leptin deficiency mice will be used to address leptin’s in vivo mechanism and the relationship between obesity, leptin, and RA inflammation. This study will provide new insights into the pathogenesis of RA and how Th17/Treg balance is regulated in lean and obesity RA patients.
摘要: Th17/Treg失衡是类风湿关节炎(RA)的重要病理机制,其失衡原因和机制是目前RA领域的研究热点。瘦素参与RA病理过程,且肥胖可上调瘦素而影响RA炎症,与RA发生发展密切相关。体外研究提示瘦素促进Th17而抑制Treg,但其分子机制、体内效果及在肥胖相关RA中的作用尚不明确。本研究以此为切入点,结合前期实验提出“瘦素可通过mTOR-SOCS-STAT信号网络调控Th17/Treg平衡”的分子机制假说,拟分选小鼠CD4+CD25+Tregs和CD4+CD25-Teffs细胞,研究瘦素对nTreg活性、iTregs和Th17分化的作用和分子机制;并分别在正常、肥胖和瘦素缺失小鼠关节炎模型中,探讨瘦素致Th17/Treg失衡的体内机制,及对关节炎炎症反应及骨损伤的影响。研究结果有助于人们理解瘦素在RA致病中的作用和机制,可为RA临床防治提供新的思路。
Th17/Treg失衡是类风湿关节炎(rheumatoid arthritis,RA)重要病理机制,其失衡原因和机制的研究可为RA防治提供新的思路。瘦素参与RA病理过程,其含量受疾病本身和患者肥胖程度的影响。体外研究提示瘦素可促进Th17而抑制Tregs,但其分子机制尚不明确。我们发现瘦素促进T细胞糖酵解,抑制其FAO,从而有助于Th17分化而抑制iTreg诱导,是导致RA患者Th17/Treg失衡的可能机制之一;并观察到禁食导致的瘦素下降可通过上调Treg细胞含量,缓解小鼠关节炎症;且首次报道了雷公藤红素,可通过mTOR,干预T细胞代谢通路,从而调控Th17/Treg平衡,作为RA临床治疗用中药,有望逆转瘦素导致的Th17/Treg失衡。另外,系统评价肥胖对RA患者治疗的影响,发现肥胖降低TNF-α拮抗剂的疗效,而不影响T细胞抑制剂或IL-6受体拮抗剂的疗效,为肥胖RA患者的个性化用药提供了循证医学证据。上述发现对RA患者Th17/Treg失衡的机制进行了全新阐释,可为RA临床防治提供新的证据和思路,具有重要科学意义和潜在临床应用价值。
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数据更新时间:2023-05-31
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