新型小分子化合物FX12靶向RNF5抑制CFTR降解在促进COPD气道粘液屏障重建中的作用及机制研究

慢性阻塞性肺病（COPD）是高发病率和高死亡率的疾病，尚缺乏有效的治疗方法。香烟烟雾（CS）诱发囊性纤维化跨膜传导调节因子（CFTR）功能障碍，促进COPD气道脱水和粘液功能障碍等病理生理改变，结合CFTR经ERAD通路降解的分子机制。提出使用小分子化合物阻断CFTR降解，增加其在细胞内表达量和通道功能，改善气道粘液屏障的科学假说。预实验结果显示小分子化合物FX12靶向RNF5泛素连接酶，阻断CFTR的泛素化降解，使其在细胞内的表达量增加，改善COPD气道上皮粘液屏障功能。本项目拟利用CS构建COPD小鼠模型，观察FX12作用后气道黏液屏障、炎性因子、肺组织病理和肺功能的变化；在体外使用人气道上皮细胞，分析FX12对CFTR离子通道数量和功能的调控作用；进一步探讨FX12对RNF5的作用及其特异性阻断CFTR的泛素化的分子机制。为深入探索COPD新治疗方案提供实验依据。

Chronic obstructive pulmonary disease (COPD) is a disease with high morbidity and mortality, and there is no effective treatment method. Cigarette smoke (CS) induced cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction can reduce mucociliary transport by depleting airway surface fluid, destroy the airway epithelial mucosal barrier, and cause mucus obstruction to promote disease. Studies have found that these defects can be corrected by enhancing CFTR. Preliminary experimental results showed that the small molecule compound FX12 blocked the ubiquitination degradation of CFTR by targeting RNF5 ubiquitin ligase and increased its expression in cells, thereby improving the pathological damage and function of COPD airway epithelial tissue.Therefore, we put forward the idea of ​​"CFTR stabilizer-FX12" to treat COPD.This project intends to use CS to construct a COPD mouse model to observe the changes in airway mucus barrier, inflammatory factors, lung tissue pathology, and lung function after FX12 is applied; human airway epithelial cells are used in vitro to analyze the number and function of FX12 on CFTR ion channels To further explore the effect of FX12 on RNF5 and the molecular mechanism of specifically blocking the ubiquitination of CFTR. This research will help explore new treatment options for COPD.