气道祖细胞丙酮酸代谢重编程促哮喘发生发展的机制研究

哮喘是一种慢性病，严重危害人类健康，无法根治，亟待突破。研究证实气道上皮黏膜的损伤与哮喘气道炎症反应的发生与持续密切相关，因此恢复气道上皮的完整有助于解决抗炎无法根治哮喘的难题。课题组前期工作证明哮喘发生发展与气道上皮祖细胞（Club细胞）功能异常有关，葡萄糖代谢决定Club细胞增殖与分化命运。预实验表明，卵清蛋白诱导哮喘小鼠模型Club细胞乳酸脱氢酶表达显著下降。基此我们提出Club细胞丙酮酸代谢重编程促哮喘发生发展的假说。项目拟以小鼠Club细胞为研究对象，采用细胞生物学，分子生物学手段和类器官模型研究丙酮酸代谢去向（产生乳酸或进入线粒体进行氧化磷酸化）对Club细胞增殖与分化功能的调控，并基因敲低小鼠模型探索Club细胞丙酮酸→乳酸途径和丙酮酸→氧化磷酸化途径对哮喘发生发展的影响，逐步揭示气道祖细胞丙酮酸代谢重编程在哮喘发生发展之间内在作用机制，从肺脏再生角度治愈哮喘寻找新出路。

Bronchial asthma, a chronic disease, is a serious danger to human health and cannot be cured so far. Studies have confirmed that airway epithelial damage is closely related to the occurrence and persistence of asthmatic airway inflammation. Therefore, restoring the integrity of airway epithelium might be helpful to solve the problem that asthma can be cured by anti-inflammatory treatments. Our previous work proved that the occurrence and progression of asthma is related to the abnormal function of Club cells, considered as airway epithelial progenitor cells, and glucose metabolism determines the fate of Club cells: proliferation or differentiation. Our preliminary experiments showed that ovalbumin induced a significant decrease in lactate dehydrogenase expression in Club cells in a mouse model of asthma. Based on this, we propose the hypothesis that reprogramming of pyruvate metabolism in Club cells promotes the development of asthma. The project intends to take mouse Club cells as the research object, and use cell biology, molecular biology methods and organoid models to study the regulation of Club cell function by pyruvate metabolism, producing lactic acid or entering mitochondria for oxidative phosphorylation. With a transgenic mouse model, we further explored the effects of the pyruvate-lactate pathway and pyruvate-oxidative phosphorylation pathway in Club cells on the development of asthma. With these attempts, we will gradually reveal the intrinsic mechanism of airway progenitor cell pyruvate reprogramming in the development of asthma, and find a new way to cure asthma through enhancing lung regeneration.