椎间盘突出是常见退变性疾病。机体退变与免疫反应及炎症关系密切，但椎间盘退变过程中是否存在免疫反应-炎症-退变环路尚不明确。课题组研究发现，退变椎间盘中存在Th17细胞招募，其分泌IL-17诱导肿瘤坏死因子TNFα产生。TNFα可通过激活NF-κB信号通路诱导金属蛋白酶ADAMTS-7产生，后者具有加重关节软骨退变作用。PGRN是一种多功能生长因子，与TNFα及 ADAMTS-7密切相关，并在类软骨相关疾病中发挥保护作用。本课题拟使用ADAMTS-7转基因及基因减低小鼠，检测ADAMTS-7在退变髓核组织表达模式及对椎间盘退变影响。通过体内外实验，明确PGRN基因缺失及PGRN重组蛋白对于椎间盘组织代谢变化，明确IL-17-TNFα-ADAMTS-7分子轴线在椎间盘退变中的作用及机制，及PGRN靶向抑制上述作用轴线的潜在价值，为进一步了解椎间盘退变发生机制提供新的线索。

Intervertebral disc herniation is a common degenerative disease in clinic. Degeneration is known to be closely associated with immune reaction and inflammation, but whether there is a immunity-inflammation-degeneration loop in degenerated intervertebral disc (IVD) still remains unclear. We have previously reported the recruitment of Th17 cells in degenerated IVD. Th17 cells can secret IL-17, which may induce the production of TNFα. It is reported that TNFα can promote the production of ADAMTS-7 through activation of NF-κB signaling pathway, and ADAMTS-7 can exaggerate cartilage degeneration. As a multifunctional growth factor, PGRN is closely related with TNFα and ADAMTS-7, and plays a protective role in various pathological processes of cartilage diseases. In the present study, we plan to use ADAMTS-7 transgenic and knockdown mice to testify the expression pattern and effect of ADAMTS-7 in IVD degeneration. Moreover, by using the recombinant PGRN protein as well as PGRN knockout mice, we plan to illustrate the function and mechanism of IL-17-TNFα-ADAMTS-7 axis in IVD degeneration, and to evaluate the therapeutic role of PGRN in IVD degeneration by targeting this axis. This study may shed a light on the mechanism and therapeutic strategy of IVD degenerative diseases in clinic.