气道粘液高分泌是慢性阻塞性肺疾病（COPD）的重要病理特征之一，增加疾病的发病率和死亡率。粘蛋白MUC5AC和MUC5B是气道粘液的主要成分，目前对其合成的调控机制的认识还很不充分，药物干预效果有限。我们近期发现，COPD患者和烟草烟雾暴露导致的COPD模型大鼠气道粘膜MUC1表达增加；MUC1基因敲除造成模型大鼠气道粘液产生增多、气流受限加重。本项目将进一步采用COPD模型大鼠、基因敲除动物、原代培养的气道上皮细胞、基因沉默和过表达、免疫共沉淀、模拟肽等工具和技术研究MUC1调控MUC5AC和MUC5B表达、抑制COPD气道粘液高分泌的分子机制，探讨MUC1模拟肽的靶向干预作用，为深入认识COPD病理机制和揭示新型治疗靶点奠定理论基础。

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles and gases. Airway mucus hypersecretion is one of important pathological features of COPD, which increases its morbidity and mortality. MUC5AC and MUC5B are main components of airway mucus. At present, the understanding of mechanisms by which MUC5AC and MUC5B syntheses are regulated is still very scant and drug interventions of their production exert limited effect. Cigarette smoking is one of the most important risk factors for COPD. Mucin 1 (MUC1)，a type I transmembrane glycoprotein，has been recognized as an epithelial cell marker. However, the role of MUC1 in regulating airway mucus hypersecretion in COPD is unknown. Interestingly, we preliminarily showed that higher MUC1 levels were observed in the airway epithelial cells of COPD patients compared to healthy controls and non-COPD subjects. Furthermore, MUC1 expression in airway epithelial cells was increased in rats exposed to cigarette smoke. Genetic knockout of MUC1 in rats led to increased mucus production and severer airflow limitation in response to cigarette smoke exposure. Therefore, we hypothesize that MUC1 attenautes cigarette smoke-induced airway mucus hypersecretion and airflow limitation, thereby relieving the progression of COPD. To this end, we will study whether and how MUC1 modulates the production of MUC5AC and MUC5B and inhibits airway mucus hypersecretion in COPD by series of tools and techniques, such as cigarette smoke-induced rat COPD model, MUC1 gene knockout rats, primary human and rat airway epithelial cells, gene silencing and overexpression as well as immunoprecipitation. Furthermore, we will investigate the targeted intervention effect of MUC1 mimetic peptide on airway mucus hypersecretion. In conclusion, the outcome of this study not only provides novel insights into the molecular mechanisms of cigarette smoke-induced airway mucus hypersecretion, but also identifies MUC1 as a therapeutic target for COPD.