基于mTOR信号探讨苗药金乌健骨胶囊对类风湿关节炎滑膜细胞自噬与凋亡的机制

Synovium of joints is the target organ in the process of rheumatoid arthritis (RA),there is sufficient evidence to show it has correlation between autophagy and apoptosis in rheumatoid arthritis synovial cells (RASF), the apoptosis rate increase after inhibiting autophagy in RASF, it testified that autophagy is involved in the regulation of apoptosis in RASF. Mammalian Target of Rapamycin(mTOR) signal is an important factor in regulating cell growth and proliferation, it involved in the regulation of growth,apoptosis,energy metabolism and cell autophagy in RASF.In view of the possible mechanisms that the mTOR signal is the key regulatory factor in RASF autophagy and apoptosis, by inhibiting mTOR signaling pathway can start RASF autophagy, and promote cell apoptosis to ease the RA synovial inflammation and bone destruction,we based on the previous clinical and experimental researches,according to the principle of "non-toxic no disease" and " remove poison as a therapy " in the miao medicine,by building RA animal models and in vitro cell model,to discuss the molecular mechanism of Miao medicine Jinwu Jiangu capsule which composed under the guidance of the theory of Miao medicine "poison" to regulate RASF autophagy and apoptosis.for this,our group propose the scientific hypothesis that Jinwu Jiangu recipe maybe maintain the balance of RASF autophagy and apoptosis by regulating the expression of related genes in mTOR signal pathway, this hypothesis is expected to explore new national medicine for the treatment of RA.

关节滑膜是类风湿关节炎（RA）发病的靶器官，有充分的证据显示类风湿关节炎滑膜细胞（RASF）自噬与凋亡存在相关性，抑制自噬后RASF凋亡增加，说明自噬参与了RASF凋亡调节。哺乳动物雷帕霉素靶蛋白（mTOR）信号是调节细胞生长和增殖的重要因素，它参与RASF生长、凋亡、能量代谢和细胞自噬的调节。针对mTOR信号是RASF自噬与凋亡的关键调节因子，抑制mTOR信号通路可以启动RASF自噬、促进细胞凋亡，从而缓解RA滑膜炎症及骨质破坏的可能机制，我们在前期临床和实验研究的基础上，根据苗医“无毒不成疾”和“毒以去为法”的原则，通过构建RA动物模型和体外细胞模型，探讨苗医“痹毒”理论指导下配伍组成的苗药金乌健骨胶囊调控RASF自噬与凋亡的分子机制。为此，课题组提出了金乌健骨方可能通过调控mTOR信号通路中相关基因的表达，从而维持RASF自噬与凋亡平衡的科学假说，有望为RA的治疗发掘新的民族药。

本项目以苗医药理论为指导，提出类风湿关节炎（RA）发病的苗医“痹毒”理论，根据苗医学“毒以去为法”的治疗原则，应用苗药组成金乌健骨方，结合课题组前期研究基础，从动物实验和细胞试验两方面阐释了金乌健骨胶囊通过调控mTOR信号介导的细胞自噬治疗类风湿关节炎的作用，为研发苗药金乌健骨方提供了新的药理作用及机制。项目通过建立胶原诱导关节炎（CIA）大鼠模型和人类风湿关节炎滑膜细胞（RASF）细胞模型，探讨mTOR信号通路中相关基因在RA关节滑膜细胞自噬与凋亡的分子机制及苗药金乌健骨胶囊对CIA大鼠关节滑膜细胞和人RASF细胞自噬的调节作用。研究取得了预期成果，明确了苗药金乌健骨胶囊能够通过调控CIA大鼠关节滑膜细胞mTOR信号通路相关基因的表达，启动CIA大鼠关节滑膜细胞自噬，促进滑膜细胞的凋亡。金乌健骨胶囊能够有效调控人RASF自噬和细胞增殖，促进细胞凋亡，进而抑制RA关节滑膜炎症和骨质破坏。.项目研究成果发表学术论文11篇，其中北大中文核心期刊5篇、SCI论文3篇、普通期刊3篇，获贵州省自然科学三等奖1项。参加学术交流8人次，培养硕士研究生5人、贵州省省管专家1名、贵州省千层次人才3名。