外泌体携带miR-124通过RhoA/ROCK信号通路调节COPD肺微血管内皮细胞凋亡的机制研究

烟草致肺微血管内皮细胞（PMECs）凋亡是COPD重要发病机制之一。肺泡上皮细胞（AECs）外泌体可调节其他细胞生物学功能。COPD中AECs外泌体对PMECs作用尚不明确。申请人观察到烟草暴露后，小鼠AECs及其外泌体中miR-124减少，AECs外泌体可促PMECs凋亡。其他疾病中，miR-124抑制RhoA/ROCK通路，促进细胞修复，并可经外泌体传递。申请人推测烟草使肺泡上皮细胞miR-124减少，通过外泌体作用于PMECs，RhoA/ROCK通路激活，引起F-actin重塑，导致PMECs凋亡，参与COPD发生发展。本项目首次从人体、动物和细胞层面探讨：COPD患者及小鼠AECs外泌体中miR-124表达；miR-124对COPD小鼠PMECs凋亡的影响；AECs外泌体携带miR-124通过RhoA/ROCK通路调控PMECs凋亡的机制。为寻找COPD的治疗新途径提供依据。

Cigarette smoking-induced abnormal apoptosis of pulmonary microvascular endothelial cells (PMECs) is an important pathological mechanism of COPD, and alveolar epithelial cells (AECs) also play an important role in the pathogenesis of COPD. Exosomes derived from AECs can regulate the biological effects of other cells. The role of exosomes derived from AECs on PMECs in COPD is not clear. Exposured to cigarette smoking, applicant had discovered that miR-124 decreased in AECs and exosomes of mice, exosomes derived from AECs promoted apoptosis of PMECs in mice. Research have reported that miR-124 can bind to and regulate RhoA/ROCK signaling pathway to mediate apoptosis, and was transmitted by exosomes between cells. Applicant speculated that in COPD, miR-124 expression was down-regulated in AECs, released by exosomes and released outside the cells and acted on PMECs, activing the expression of RhoA/ROCK signaling pathway,causing apoptosis of PMECs, involved in the pathogenesis of COPD. This study will be firstly explored from human, animals and cells: miR-124 expression in AECs and exosomes in COPD patients and mice, apoptosis of PMECs; the effects of exosomal miR-124 derived from AECs on apoptosis of PMECs in COPD model mice; the molecular mechanism of exosomal miR-124 regulating apoptosis of PMECs through RhoA/ROCK signaling pathway. This project will provide experimental evidence for finding new ways to treat COPD.