应力激活circRNA_GCN1L1引发炎症和力反应失衡协同促进颞下颌骨关节炎发生的机制研究

颞下颌骨关节炎（TMJOA）是影响张口和咀嚼功能的难治病，机械应力和炎症共同作用是发病的主要原因，但分子机制未明。我们前期发现TMJOA患者的滑膜中circGCN1L1（cG1）显著高表达，且在体外应力刺激后明显上调并激活TNFα介导的炎症通路；生信分析和点突变证实miR-330是其重要的效应靶标，可调控下游TNFα和Piezo2的表达。由此提出应力诱导cG1通过miR-330分别导致炎症加剧和力反应失衡，协同促进TMJOA发生的假说。本研究拟结合临床标本、TMJOA模型和Mir330KO小鼠等明确：1）应力如何上调cG1的表达及其主要的信号通路和分子机制；2）cG1在TMJOA进展中的调控作用；3）cG1通过miR-330家族分别调控Piezo2和TNFα表达协同促进TMJOA发生的机制；4）cG1和miR-330作为靶点对炎症和应力感应双重抑制的治疗价值。为TMJOA的诊治提供新思路。

Temporomandibular joint osteoarthritis (TMJOA) is a refractory disease affecting mouth opening and masticatory function. Mechanical stress and synovitis are the main reasons to cause TMJOA, but the underlying molecular mechanism remains poorly understood. Our previous study has found that circGCN1L1 (cG1) expressed most significantly high in TMJOA patients’ synovium. It can be upregulated under the induction of mechanical stress and activate TNFα mediated inflammatory pathway. Bioinformation analysis and point mutation verified that miR-330 family was an important effect target of cG1 and may regulate downstream TNFα and Piezo2 expression. We thus propose a working model that mechanical stress stimulates cG1 overexpression and inhibits miR-330 family activity, which in turn leads to collaboration of the inflammation and mechanical stress imbalance in the promotion of TMJOA. In this project, by the combination of clinical specimen, TMJOA animal model and Mir330 knockout mice, we will first elucidate how the mechanical stress upregulates cG1 and its signal pathway and molecular mechanism. Second, we will explore the relationship between cG1 and TMJOA progressing. Third, we will study the working mechanism of cG1 regulating Piezo2 and TNFα expression through absorbing miR-330 family in the collaboration of TMJOA development. At last, we will express the value of cG1 and miR-330 as treatment targets to double inhibit inflammation and mechanical reaction. Over all this project will bring new ideas of diagnosis and therapy for TMJOA.