靶向TRB3介导的蛋白相互作用抗肺纤维化的作用和机制

Pulmonary fibrosis is considered as not only an independent disorder but also the crucial pathological change in a diversity of chronic fibro-proliferative lung diseases. Unfortunately, none medication was accepted to reverse pulmonary fibrosis. Persitent and repeated injury to the alveolar epithelium and inflammation are the leading causes for the development and progression of pulmonary fibrosis. Ubiquitin proteasome system (UPS) and autophagy are both critical ways for clearance of pathogens, injured/aged organelles, misfolded proteins and other biomacromolecules as considering a cytoprotective mechanism against chronic inflammation and lung fibrosis. Our preliminary studies indicate that TRB3, a stress response protein, could interact with many E3 Ubiquitin ligases and autophagy related proteins to interfere UPS function and block autophagic flux, which may prevent the degradation of pro-fibrosis protein and extracellular matrix in the cells. Base on these finding, we have designed a strategy to select new drug targets based on the interaction between TRB3 and key proteins, and we will identify the reliability of these new drug target, with a depth-analysis of their biological function using different models and clinical samples. We will also do a high-throughput screening to identify leading compounds that interfere TRB3 mediated protein-protein interactions and are thus potential new drugs. The results driven from these studies not only help us to further understand the pathogenesis of pulmonary fibrosis, but also provide a new possibility for clinical therapy.

肺纤维化既是独立疾病，也是多种慢性肺病的基本病理改变。目前没有公认能逆转肺纤维化的药。反复肺损伤－修复和炎症反应是肺纤维化发生发展的主要原因。泛素蛋白酶体系统和自噬是清除细胞内受损细胞器、错误折叠蛋白和其它生物大分子的重要途径，是机体对抗炎症和纤维化的主要机制。我们发现应激蛋白TRB3与多种E3泛素连接酶及自噬相关蛋白相互作用，干扰泛素蛋白酶体系统功能并阻断自噬流，妨碍细胞内促纤维化蛋白降解。基于上述工作基础，本项目拟寻找肺纤维化发病中与TRB3相互作用的关键蛋白，确定这些蛋白-蛋白相互作用是否能成为抗肺纤维化新药靶，深入分析这些药靶的功能，并使用转基因动物和临床样本鉴定这些靶点的可靠性。我们还将筛选干扰TRB3与关键蛋白相互作用的先导化合物，并验证其抗肺纤维化作用。本项目不仅要深入研究肺纤维化发病机制，更有可能通过鉴定全新药靶，发现抗肺纤维化的全新先导化合物，为临床治疗提供新契机。

肺纤维化既是独立疾病，也是多种慢性肺病的基本病理改变。目前没有公认能逆转肺纤维化的药。反复肺损伤－修复和炎症反应是肺纤维化发生发展的主要原因。泛素蛋白酶体系统和自噬是清除细胞内受损细胞器、错误折叠蛋白和其它生物大分子的重要途径，是机体对抗炎症和纤维化的主要机制。我们发现应激蛋白TRB3与多种E3泛素连接酶及自噬相关蛋白相互作用，干扰泛素蛋白酶体系统功能并阻断自噬流，妨碍细胞内促纤维化蛋白降解。基于上述工作基础，本项目寻找了肺纤维化发病中与TRB3相互作用的关键蛋白，并确定这些蛋白-蛋白相互作用是否能成为抗肺纤维化新药靶，同时本项目深入分析这些药靶的功能，并使用转基因动物和临床样本鉴定这些靶点的可靠性。我们还筛选到干扰TRB3与关键蛋白相互作用的先导化合物，并确定其抗肺纤维化作用。本项目不仅深入研究肺纤维化发病机制，更有通过鉴定全新药靶，发现抗肺纤维化的全新先导化合物，为临床治疗提供新契机。