BMP/Wnt 信号内稳态破坏导致小鼠肺气肿的机制

Despite pulmonary emphysema is a main feature of chronic obstructive pulmonary disease (COPD)，which is the fourth cause of death in the world, the cellular and molecular mechanisms of pulmonary emphysema remain elusive. We have recently generated a genetically modified mouse model, SP-C-rtTA;(tetO)7-Cre;pMes- Noggin, which overexpresses Noggin and result in down-regulation of both BMP/Smad and Wnt/β-catenin in the adult pulmonary epithelium. These mice developed severe emphysema over time, which was similar to the course of emphysema commonly observed in human. In this proposal, we design a serial experiments aiming to: 1) confirm pathological features by analyzing pathogenesis of pulmonary emphysema in this mouse line; 2) rescue emphysema phenotype of these mice by respectively or spontaneously increasing BMP/Smad or/and Wnt/β-catenin signaling in the pulmonary epithelium using pMes-BMPRIa and/or Axin2lacZ mouse line; 3) reveal the cellular and molecular mechanism underlying; 4) investigate the possibility of developing specific target-oriented therapies by decreasing BMP/Smad and Wnt/β-catenin signaling using small molecules. The results obtained from the proposed studies will significantly advance our current understanding of the homeostastic roles of BMP and Wnt signaling in pulmonary emphysema and will also shed lights on future designs of therapeutic strategy and medicine in prevention and cure of pulmonary emphysema in human.

肺气肿是造成慢性阻塞性肺疾病的主要病因，发病率高，是导致死亡的第四大病因。目前对肺气肿发病的细胞及分子病理机制所知甚少。前期构建了成体肺上皮过表达Noggin的转基因小鼠，表现出典型的肺气肿病理特征。期望通过研究，解释和阐明该小鼠的肺气肿症状的病理进程如何，能在多大程度上模拟人类的肺气肿疾病；肺部BMP/Smad和Wnt/β-catanin信号活性的下降是否为肺气肿发生的主要病理基础，提高这2条信号通路可否挽救肺气肿的病变；BMP/Smad和Wnt/β-catanin下调所导致肺气肿病变的分子机制是什么? BMP/Smad和Wnt/β-catanin信号通路可否作为肺气肿疾病药物治疗的靶点？研究结果将有可能弥补肺气肿研究中动物模型的不足，并深入探究肺气肿的发病机理、期间的组织病变和炎症反应与BMP及WNT信号内稳态之间的关系，为进一步开发肺气肿和COPD的药物治疗提供条件和可能

肺气肿是造成慢性阻塞性肺疾病的主要病因，发病率高，是导致死亡的第四大病因。本项目前期构建了成体肺上皮过表达Noggin的转基因小鼠，表现出典型的肺气肿病理特征。经过两年的研究表明，Noggin的过表达将下调肺II型上皮细胞的WNT 和BMP信号的活性水平，而这两种信号活性水平的降低是小鼠肺气肿疾病产生的病理基础。该小鼠的疾病，随着时间的推移病情将会加重，能够较好地模拟人肺气肿疾病。模型小鼠的肺部表现出氧化-抗氧化的失衡，具有明显的炎症反应，而且其胶原蛋白、弹性蛋白、纤维连接蛋白等胞外基质蛋白减少，小鼠肺的增殖和凋亡水平均增高。用过表达BMP和WNT的遗传小鼠分别挽救或者同时挽救肺气肿模型小鼠，发现病情均能改善。同时，用提高BMP活性水平的异甘草素联合提高WNT活性水平的LiCl能够明显预防或者治疗该模型小鼠的肺气肿疾病。实验结果证实BMP及WNT信号内稳态的改变将导致肺气肿疾病的发生，而小分子药物的疗效将为进一步开发肺气肿和COPD的药物治疗提供条件和可能。