Role of ion channels in the development of COPD

描述（由申请人提供）：超过1200万美国人患有慢性阻塞性肺疾病（COPD）。虽然大约五分之一的吸烟者会发展成COPD，但吸烟占COPD发展的90%。我们有证据表明，囊性纤维化跨膜传导调节因子（CFTR）的表达在COPD患者的人体样本中受到抑制，香烟烟雾降低了肺上皮细胞中CFTR的表达。CFTR是主要在上皮细胞中表达的氯离子通道，其调节流体稳态。CFTR功能的丧失与肺中粘液的积聚、异常炎症和伤口修复相关。因此，香烟烟雾诱导的CFTR异常在吸烟相关疾病的病理生理学中的潜在重要性应进一步评估。超过1000万美国人是CFTR突变的无症状携带者。这表明吸烟会进一步降低CFTR蛋白的表达，并可能导致肺部疾病的风险增加。本研究将使用表达减少或不表达CFTR蛋白的小鼠模型评估CFTR对COPD发展的贡献。该提案还将确定CFTR在吸烟肺反应中的作用。这些研究将确定新的标记物，可以作为治疗的目标。

DESCRIPTION (provided by applicant): Over 12 million Americans have chronic obstructive pulmonary disease (COPD). Although approximately 1 out of 5 cigarette smokers develop COPD, smoking accounts for 90% of development of COPD. We have evidence that the expression of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is suppressed in human samples from COPD patients and that cigarette smoke reduces the expression of CFTR in lung epithelial cells. CFTR is a chloride channel that is primarily expressed in epithelial cells where it regulates fluid homeostasis. Loss of CFTR function is associated with accumulation of mucus in the lung, abnormal inflammation and wound repair. Therefore, the potential importance of cigarette smoke-induced CFTR abnormalities in the pathophysiology of smoking-related diseases should be further evaluated. Over 10 million Americans are asymptomatic carriers of one CFTR mutation. This implicate that cigarette smoking will further decrease CFTR protein expression and might lead to increased risk of pulmonary diseases. This study will assess the contribution of CFTR to the development of COPD using a mouse model expressing reduced or no CFTR protein. This proposal will also identify the role of CFTR in lung responses to cigarette smoking. These studies will identify new markers that could be targeted for therapy.