大骨节病关节软骨细胞自噬缺陷不同于骨关节炎，分子机制不明，缺乏有效干预方法。课题组预实验发现大骨节病关节软骨自噬蛋白ATG4C的表达及功能异常。本项目采用流行病学调查、基因蛋白检测、细胞培养、转染、RNA干扰和动物实验技术，研究自噬蛋白ATG4、LC3在成人大骨节病软骨细胞自噬缺陷中的作用及调控机制，探索自噬干预防治大骨节病新方法。内容包括：①ATG4、LC3在成人大骨节病软骨细胞自噬缺陷和过度凋亡中的作用及机制；②ATG4、LC3在T-2毒素损伤关节软骨中的作用及机制；③雷帕霉素、氨基葡萄糖对成人大骨节病自噬缺陷及T-2毒素损伤关节软骨的干预效果。本项目验证“ATG4、LC3介导的自噬体成熟机制异常—软骨细胞自噬缺陷，内稳态失衡—关节软骨退行性变”的大骨节病致病途径新假说，可推进深入认识大骨节病关节软骨损伤的分子机制，为自噬干预防治大骨节病研究提供科学依据，具有重要的科学意义和应用价值。

The autophagic defects of articular chondrocytes of Kashin-Beck disease (KBD) differ from that of osteoarthritis. The molecular mechanism of autophagic defects of KBD remain unclear now, resulting in the lack of effective intervention approaches. The pre-experiments of our research group observed abnormal expression and function of autophagy-related protein ATG4C in KBD articular cartilage. Using epidemiologic investigation, determination of genes and proteins, cell culture, cell transfection, RNA intervenion and animal experiment technologies, this project will investigate the roles and regulatory mechanism of autophagy-related proteins ATG4,LC3 in the autophagic defects of adult KBD, and explore novel autophagic intervention–based approaches for preventing and treating KBD. The main study contents include:(1) the roles and mechanism of ATG4,LC3 in the autophagic defects and excessive apoptosis of KBD chondrocytes; (2) the roles and mechanism of ATG4,LC3 in T-2 toxin induced articular cartilage damages; (3) the intervention effects of rapamycin and glucosamine for autophagic defects of adult KBD and T-2 toxin induced articular cartilage damages. This project aims to verify the novel KBD pathogenic pathway hypothesis, that is "dysfunction of ATG4,LC3 mediated autophagosome mature - autophagic defects and homeostasis imbalance of chondrocytes - degeneration of articular cartilage". The study results will promote deeply understanding the molecular mechanism of articular cartilage damages of KBD, and provide scientific basis for the studies of preventing and treating KBD using autophagic intervention approaches,which have important scientific significance and application value.