CircRNA-0014591调控miR-218在吸烟所致COPD中作用机制研究

Cigarette smoking is one of serious public health problems, which can cause chronic obstructive pulmonary disease(COPD). Airway remodeling is one of well-documented pathologies in COPD, which is caused by cigarette smoke (CS)-induced epithelial-mesenchymal transition (EMT) of airway epithelial cells, however, which molecular mechanisms remain unclear. There are very few investigative publications about the roles and mechanisms of circular RNAs(circRNAs) and microRNAs(miRNAs) in cigarette smoking-induced damages. Based on our preliminary results, using the cells model of cigarette smoke extract(CSE)-induced EMT in human bronchial epithelial (HBE) and the animal model of CS-induced COPD , we are going to systematically investigate the roles of EMT in airway epithelial cells mediated by circRNA-0014591-regulated miR-218, which induces airway remodeling in cigarette smoking-induced COPD, by down-regulating circRNA-0014591 or/and up-regulating miR-218 in vitro and in vivo, respectively. Our results will be helpful to understand the molecular mechanisms underlying cigarette smoking-induced COPD, which will provide new basis to find the early biomarkers and new measures of preventing and treating the cigarette smoking-induced lung damage.

吸烟是危害健康的严重公共卫生问题，其可引起慢性阻塞性肺病(COPD)，而气道重塑是COPD的主要病理特征之一。香烟烟雾(CS)可引起气道上皮细胞发生上皮-间质转化(EMT)而诱导气道重塑，但其具体分子机制尚不明确。环状RNAs(circRNAs)与微小RNAs(miRNAs)及其调控关系在吸烟所致机体损伤中作用机制研究报道甚少。本项目在以往研究工作基础上，利用已建立香烟烟雾抽提物(CSE)所致人支气管上皮(HBE)细胞发生EMT细胞模型和CS所致小鼠COPD模型，进一步探讨下调circRNA-0014591或/和上调miR-218等干预处理对细胞和动物模型的影响，从而较系统地探讨circRNA-0014591调控miR-218介导气道上皮细胞发生EMT引起气道重塑在吸烟所致COPD中的作用，以揭示吸烟所致COPD的部分分子机制，为寻找吸烟所致肺损伤的早期生物标志及发现新的治疗靶标提供依据。

吸烟是一种严重危害人类健康的不良生活方式，已成为全世界公共卫生问题之一。气道重塑和肺气肿及COPD是吸烟最常见和最严重的疾病，但其发病机制不清楚，而且目前对吸烟所致健康危害尚无有效的预防和治疗药物。.本项目利用香烟抽提物（CSE）急性和慢性处理人支气管上皮细胞（HBE）、肺泡上皮细胞（A549和MLE-12）发生上皮间质转化（EMT）、自噬、凋亡和衰老，CSE处理HBE细胞与巨噬细胞（THP-1）共培养及外泌体处理，并采取多种干预处理的细胞实验；不同程度香烟烟雾（CS）慢性暴露所致小鼠气道重塑和肺气肿及COPD以及多种干预处理的动物实验；不同程度吸烟的COPD人群肺功能、血清和肺组织。.探讨了以下内容：（1）Circ0061052通过miR-515-5p调控FoxC1/Snail通路在吸烟所致HBE细胞EMT及COPD气道重塑中的作用机制；探讨了miR-125a-5p通过Sp1调控SIRT1/HIF-1a介导肺泡上皮细胞衰老在吸烟所致肺气肿及COPD中作用机制；（3）circRNA_0026344调控miR-21介导自噬和凋亡在吸烟所致肺气肿及COPD中作用机制；（4）METTL3介导m6A调控外泌体miR-93介导上皮细胞与巨噬细胞cross-talk异常在吸烟所致肺气肿中的作用机制。从而在细胞、整体动物和人群三个水平系统地探讨吸烟所致气道重塑和肺气肿及COPD的分子机制。.获得的研究结果揭示了吸烟所致气道重塑、肺气肿及COPD发生发展的部分分子机制，并为寻找吸烟所致健康危害的早期生物标志和发现新的防治措施提供新线索。研究结果不仅对于吸烟而且对于环境有害因素所致机体损害防控具有重要的科学意义和一定的应用价值。