Molecular Pathogenesis and Phenotype of Acquired CFTR Dysfunction in COPD

描述（由申请人提供）：囊性纤维化跨膜调节剂（CFTR）活性强效调节剂的开发，提高了CFTR功能的药理学增强可能具有重要临床意义的可能性，即使在没有CF基因先天性突变的个体中也是如此。能够通过CFTR强烈刺激氯化物分泌的新药物为常见的粘液淤积疾病（包括烟草暴露引起的慢性阻塞性肺疾病（COPD））提供了新的治疗策略。本研究提出的初步数据表明，COPD和烟草暴露患者体内和体外CFTR活性降低，获得性CFTR功能障碍可能与COPD发病有关。我们实验室最近的结果也表明，分子VX-770增强CFTR，一种被证明可以拯救G551D-CFTR控制突变的CF患者的基本缺陷的药物，可以恢复香烟烟雾暴露后的CFTR功能，这为COPD患者提供了一种潜在的新治疗策略。在这些研究中，我们将研究烟草烟雾暴露诱导黏液停滞的假设，这是由于一些COPD患者的CFTR功能障碍的获得性状态，而这种状态可以通过应用CFTR通道门控的增强剂来逆转。在Aim 1中，我们将通过测定COPD患者支气管内CFTR活性和表达来确定下气道CFTR缺乏症的患病率和严重程度。研究将包括吸烟和不吸烟的COPD患者、健康吸烟者和正常对照，并将建立与获得性CFTR功能障碍相关的COPD亚表型。在Aim 2中，我们将利用细胞培养模型和高度预测体内结果的组织，确定烟草烟雾暴露导致获得性CFTR功能障碍的细胞机制，并测试CFTR功能障碍是否可以通过给予VX-770（一种CFTR门控增强剂）逆转。在Aim 3中，我们将使用我们开发的表征肺上皮基本特性的新方法，研究烟草暴露和CFTR调节对气道表面液体调节、粘液运输和粘液流变的下游影响。研究结果将定义由CFTR功能障碍引起的COPD临床特征，这种现象的机制，以及CFTR增强剂逆转这种缺陷的倾向。该提案的完成将建立一种新的COPD亚表型，并为COPD的新治疗模式奠定基础。

DESCRIPTION (provided by applicant): The development of potent modulators of cystic fibrosis transmembrane regulator (CFTR) activity has raised the possibility that pharmacologic enhancement of CFTR function may have important clinical significance, even among individuals without congenital mutations in the CF gene. New pharmacologic agents capable of robustly stimulating chloride secretion through CFTR point to novel treatment strategies for common diseases of mucus stasis, including chronic obstructive pulmonary disease (COPD) caused by tobacco exposure. Preliminary data presented in this application establish that patients with COPD and tobacco exposure exhibit reduced CFTR activity in vivo and in vitro and that acquired CFTR dysfunction may contribute to COPD pathogenesis. Recent results from our laboratory have also shown that potentiation of CFTR with the molecule VX-770, an agent shown to rescue the basic defect in CF patients with the G551D-CFTR gating mutation, can restore CFTR function following cigarette smoke exposure, suggesting a potential new therapeutic strategy for individuals with COPD. In these studies, we will investigate the hypothesis that tobacco smoke exposure induces mucus stasis due to an acquired state of CFTR dysfunction in some individuals with COPD, and this state can be reversed by application of a potentiator of CFTR channel gating. In Aim 1, we will define the prevalence and severity of CFTR deficiency in the lower airway by determining intrabronchial CFTR activity and expression in the setting of COPD. Studies will include COPD patients who do and do not actively smoke, healthy smokers, and normal controls, and will establish the COPD sub-phenotype associated with acquired CFTR dysfunction In Aim 2, we will determine the cellular mechanisms underlying acquired CFTR dysfunction by tobacco smoke exposure using cell culture models and tissues highly predictive of in vivo results, and test whether CFTR dysfunction can be reversed by administration of VX-770, a potentiator of CFTR gating. In Aim 3, we will investigate downstream effects of tobacco exposure and CFTR modulation on airway surface liquid regulation, mucus transport, and mucus rheology using novel methods we have developed to characterize basic properties of pulmonary epithelia. Results will define COPD clinical characteristics attributable to relative CFTR dysfunction, the mechanisms that underlie this phenomenon, and the propensity of CFTR potentiators to reverse this defect. Completion of the proposal will establish a novel COPD sub-phenotype and set the stage for a new treatment paradigm in COPD.