Molecular mechanisms of wasting in experimental COPD

慢性阻塞性肺疾病（COPD）是一个主要的全球性健康问题，预计到2020年将成为世界上第三大死亡原因。吸烟是COPD的主要原因，占工业化国家病例的95%以上。目前没有治疗方法可以阻止疾病的不可避免的进展。迄今为止，大多数研究都集中在这种疾病导致肺部破坏的方面，但越来越明显的是，COPD是一种多器官疾病。直到最近，人们普遍认为，COPD患者运动耐量的严重丧失是由于继发于肺结构损伤的气体交换受损。瘦体重（肌肉）的损失现在被认为是COPD的主要合并症，也是功能障碍的直接原因，患者的生活质量明显恶化，死亡率增加，呼吸困难和运动耐量降低。骨骼肌萎缩是COPD死亡率的一个强有力的预测因子，与肺功能损害无关。尽管肌肉萎缩的临床严重性和提示性证据表明它可能是可逆的，但对致病机制知之甚少。因此，本项目的目标是使用COPD的实验模型来确定消耗的分子基础，以恢复骨骼肌的稳态。从这项研究提案中获得的见解可能会导致识别潜在的新靶点，用于预防和逆转COPD骨骼肌萎缩的衰弱和危及生命的影响。对于COPD患者，这有可能提高生活质量、功能能力和预期寿命。

Chronic obstructive pulmonary disease (COPD) is a major global health problem and has been predicted to become the third largest cause of death in the world by 2020. Cigarette smoking is the major cause of COPD and accounts for more than 95% of cases in industrialized countries. Currently no therapies exist to halt the inevitable progression of the disease. To date most of the research has focused on the aspects of this disease which result in destruction of the lung however it is becoming increasingly evident that COPD is a disease of multiple organs. Until recently it had been widely believed that the profound loss of exercise tolerance observed in COPD patients was due to impaired gas exchange secondary to lung structural damage. Loss of lean body mass (muscle) is now recognised as a major co-morbidity of COPD and a direct cause of functional impairment with patients suffering marked deteriorations in quality of life, increased mortality, breathlessness and decreased exercise tolerance. Skeletal muscle wasting is a powerful predictor of mortality in COPD, independent of the lung function impairment. Despite the clinical seriousness of muscle wasting and suggestive evidence that it may be reversible, little is known about the pathogenic mechanisms. Therefore the goal of this project is to use experimental models of COPD to identify the molecular basis of wasting, in order to restore skeletal muscle homeostasis. The insights gained from this research proposal may lead to the identification of potentially novel targets for the prevention and reversal of the debilitating and life threatening effects of skeletal muscle wasting in COPD. For the COPD patient this has the potential to increase quality of life, functional ability and life expectancy.