白介素37在主动脉瓣间质细胞中对Toll样受体介导的成骨反应的抑制作用及机制

钙化性主动脉瓣疾病(CAVD)患病率日益增高，严重影响人们健康。我们前期研究表明激活Toll样受体（TLR）2和4能诱导成骨反应，而成骨反应在CAVD发病过程起重要作用。人白介素37（IL-37）是近期发现的抑炎因子，前期研究提示IL-37在CAVD病变细胞表达明显降低，然而IL-37能否抑制TLR2/4介导的成骨反应以及作用机制是什么均尚待研究。本研究将通过运用IL-37蛋白多肽、基因沉默、过表达等技术检测IL-37在主动脉瓣间质细胞中能否抑制TLR2/4介导的成骨反应；建立CAVD疾病小鼠模型并检验IL-37转基因是否对该疾病模型有保护作用；应用免疫共沉淀等方法探讨IL-37发挥作用的机制，拟证明IL-37可通过IL-18R/SIGIRR轴抑制TLR2/4介导的成骨反应，对CAVD起保护作用。该研究将丰富IL-37和CAVD的理论，为进一步认识CAVD的发病机制和防治该病提供新的思路。

Calcific aortic valve disease (CAVD) affects a large number of old people and has increased in prevalence. However, the mechanism of pathogenesis of CAVD remains unclear and therapeutic drugs are currently unavailable. Our previous studies demonstrated that stimulation of Toll-like receptors (TLR) 2/4 induces augmented osteogenic responses in human interstitial cells of stenotic aortic valves. Osteogenic responses play important roles in the pathogenesis of CAVD. Recent studies demonstrated that human interleukin 37 (IL-37) has a novel anti-inflammatory effect. However, whether IL-37 suppresses the osteogenic responses and how it exerts an effect in human aortic valve interstitial cells (AVICs) remains unknown. In this study, we will examine whether IL-37 regulates TLR 2/4-mediated osteogenic responses in aortic valve interstitial cells by applying exogenous IL-37 peptide, IL-37 silencing/overexpression. Next, we will try to set up a CAVD mouse model and test whether IL-37 has a protective effect on this model. Finaly, we will investigate the underlying mechanisms by which IL-37 exerts an effect in aortic valve interstitial cells. Our study attempts to demonstrate that IL-37 deficiency plays an important role in the pathogenesis of CAVD and that IL-37 has therapeutic potential in the prevention of progression of CAVD by suppressing TLR2/4-mediated osteogenic responses via the IL-18R/SIGIRR axis. The results of this study will provide new insights in the pathogenesis of CAVD and provide new strategies for the prevention and therapy of this disease.