IL-17RC基因多态性在胸椎后纵韧带骨化症易感性中的机制研究

胸椎后纵韧带骨化症（T-OPLL）发病隐匿、致残率高，手术治疗风险极大。目前其病因仍不明确，我们在前期研究工作中对T-OPLL患者行全基因组测序，筛选发现IL-17RC基因单核苷酸多态性（SNP）位点（rs199772854 C>A）与T-OPLL致病相关，但其具体作用机制尚不清楚。本项目预实验研究发现，该SNP的存在可通过瘦素与T-OPLL易感性发生内在关联，同时其可增强机体IL-17信号活性、上调成骨前体细胞中成骨标志物表达水平及成骨活性，且瘦素在其中发挥协同效应。鉴于既往研究发现IL-17和瘦素对JAK-STAT通路的共同调控及JAK-STAT在成骨分化中具有潜在调节作用，后续我们拟深入研究该SNP激活IL-17信号后是否介导JAK-STAT通路活化影响细胞成骨分化过程。通过本研究以期揭示IL-17RC基因SNP在T-OPLL易感性中的作用及机制，为该病非手术治疗奠定理论基础。

Thoracic ossification of the posterior longitudinal ligament (T-OPLL) is characterized by occult onset and a high disability rate, and the surgical treatment remains challenging. The pathogenesis of T-OPLL is still unclear. In our previous study, whole-genome sequencing of T-OPLL revealed that the single nucleotide polymorphism (SNP) of IL-17RC gene (rs199772854 C>A) was remarkably correlated with the occurrence of T-OPLL; nevertheless, the underlying mechanism remains unknown. Our preliminary studies found that this SNP may be intrinsically associated with predisposition to T-OPLL through leptin. Meanwhile, the existence of this SNP could enhance the IL-17 signal activity, and up-regulate the expression of osteogenic markers and the osteogenic activity in osteogenic precursor cells, during which leptin played a synergistic effect. In view of the co-regulation of IL-17 and leptin on the JAK-STAT signaling pathway and the potential regulatory role of JAK-STAT pathway in osteogenic differentiation, we intend to investigate whether the SNP-activated IL-17 signal activity can affect the osteogenic differentiation through the JAK-STAT pathway. This study is expected to reveal the role and mechanism of IL-17RC SNP in T-OPLL susceptibility, which may lay a theoretical foundation for non-surgical therapy of T-OPLL.