自噬介导去毒附子汤调控滑膜成纤维细胞ATG12-IRF1-VCAM1轴干预老年膝骨关节炎的机制研究

膝骨关节炎（KOA）是好发于老年人的退行性疾病，是骨科临床难题。滑膜炎症是老年KOA的主要特征和干预途径，但现有药物疗效有限，无法满足临床需求。自噬衰退是老年KOA滑膜炎症发生和进展的重要诱因，激活自噬能有效缓解滑膜炎症及关节退变。申请人前期首次发现自噬蛋白ATG12通过互作调控IRF1转录活性，参与VCAM1介导的滑膜炎症，该分子路径可能是老年KOA滑膜炎症的关键干预靶点。KOA属中医“骨痹”，适用散寒止痛之法。经方附子汤能有效改善KOA滑膜炎症及关节退变。团队建立去毒附子汤，证明该方能激活滑膜自噬，并提出假说：自噬ATG12-IRF1-VCAM1轴是介导老年KOA滑膜炎症进展及去毒附子汤干预的关键机制。申请人拟通过动物、细胞及分子实验验证该假说，探究去毒附子汤对老年KOA自噬的调控机制，旨在完善KOA自噬相关病机和中药干预的科学内涵，为临床应用去毒附子汤防治老年KOA提供实证依据。

Knee osteoarthritis (KOA) is an aging related degenerative disease and unsettled topic in orthopedic clinic. Synovitis is an important characteristic as well as intervention indicator of senile KOA. However, limited efficacy of the existing drugs disappoints these clinical KOA patients. Autophagy decline is one of the main causes of synovitis in senile KOA. Autophagy restoration is considered as potential intervention of synovitis and joint degeneration. The applicant found for the first time that autophagy protein ATG12 regulated VCAM1-mediated synovitis through protein interaction with IRF1, upstream transcriptional factor of VCAM1. KOA is defined as bone bi-disease in traditional Chinese medicine (TCM), so that therapies dispersing cold and pain have been considered as targeted TCM cure for KOA. Detoxified Fuzi decoction is prepared with Fuzi produced through self-designed detoxification process. While applied in KOA rats, detoxified Fuzi decoction shows promising efficacy in relieving synovitis and joint degeneration in KOA. The applicant has also proved that detoxified Fuzi decoction could activate autophagy in synovial fibroblasts. Taken together, we hypothesize that detoxified Fuzi decoction activates autophagic ATG12-IRF1-VCAM1 axis in synovial fibroblasts to inhibit synovitis in senile KOA and related joint degeneration. Through animal, cellular and molecular studies, we aim to reveal the mechanism of detoxified Fuzi decoction in the regulation of autophagic ATG12-IRF1-VCAM1 axis. We also hope to replenish the scientific connotation of autophagy-related pathogenesis and intervention of senile KOA, and provide experimental evidences for the clinical application of detoxified Fuzi decoction in senile KOA.