Translational Program in CFTR-Related Airway Diseases

项目总结/摘要 囊性纤维化跨膜传导调节因子（CFTR）通过以下途径维持上皮功能： 作为上皮细胞顶端表面的离子通道，并控制 粘液及其清除。CFTR的基因突变导致CF，这些突变也 通过改变宿主防御而导致其他气道疾病。我们帮助发现， CFTR功能障碍也可以在没有先天性突变的情况下获得，导致 慢性阻塞性肺疾病慢性支气管炎表型的发病机制 （COPD）。为此，该研究计划将在阐明 与遗传和获得性CFTR功能障碍相关的气道疾病的发病机制， 应用这些知识来开发新的诊断和治疗工具。该计划将 包括两个重点领域的关键使命的NHLBI。第一个将解决基本的 使用CF作为模型，围绕粘液清除的问题。我们将在体内实施 μOCT成像，我们共同发明的一种技术，提供了前所未有的视野， 气道表面的功能显微解剖学;执行创新技术以探测气道 粘液;并使用一种新的CF大鼠，其表现出粘液清除延迟和遗传缺陷， 随着时间的推移发展的宿主防御，以1）阐明控制 粘液及其清除，2）开发针对异常粘液的新治疗方法 本身，和3）建立机制的敏感性增加慢性细菌 感染和细菌根除的新策略。在第二个重点领域，我们将研究 这些途径在慢性支气管炎中的作用，慢性支气管炎是一种流行的疾病，缺乏治疗， 逆转其自然历史。我们将确定1）获得性CFTR功能障碍对 雪貂，第一个慢性支气管炎动物模型，2）粘液淤滞在 人COPD气道（并与CF对比），3）获得性CFTR功能障碍是否增加 COPD雪貂对慢性细菌感染或呼吸恶化的易感性，以及4） 测试慢性支气管炎的新疗法，包括先进的CFTR增效剂， 适应症这些研究之间将产生重大的协同作用，不仅将雇用 尖端技术和动物模型，同时利用我们公认的专业知识 在CFTR导向疗法的一流人类研究中领先。注意到罗医生的 成功的一贯记录;他的实验室的创新，独一无二的能力; 和建议目标的直接可行性，该计划承诺将改变 领域和发现的治疗，提供重大改善的持续时间和生活质量。

PROJECT SUMMARY / ABSTRACT Cystic fibrosis transmembrane conductance regulator (CFTR) maintains epithelial function by acting as an ion channel at the apical surface of epithelial cells, and governs the formation of mucus and its clearance. Genetic mutations of CFTR cause CF, and these mutations also contribute to other airway diseases by altering host defense. We have helped discover that CFTR dysfunction also can be acquired in the absence of congenital mutations, contributing to the pathogenesis of the chronic bronchitis phenotype of chronic obstructive pulmonary disease (COPD). To this aim, this Research Program will make decisive advancements in elucidating the pathogenesis of airway diseases linked to genetic and acquired CFTR dysfunction, and will apply this knowledge to develop new tools for their diagnosis and treatment. The Program will encompass two focus areas critical to the mission of the NHLBI. The first will tackle fundamental questions surrounding mucus clearance, using CF as the model. We will implement in vivo μOCT imaging, a technique we co-invented that provides an unprecedented view of the functional microanatomy of the airway surface; perform innovative techniques to probe airway mucus; and use a novel CF rat that exhibits delayed mucus clearance and an inherit defect in host defense that develops over time to 1) illuminate mechanisms governing the formation of mucus and its clearance, 2) develop novel therapeutic approaches targeting abnormal mucus itself, and 3) establish mechanisms underlying increased susceptibility to chronic bacterial infection and novel strategies for bacterial eradication. In the second focus area, we will study the role of these pathways in chronic bronchitis, a prevalent disorder that lacks treatments that reverse its natural history. We will determine 1) the impact of acquired CFTR dysfunction in ferrets, the first animal model of chronic bronchitis, 2) mechanisms of mucus stasis in the human COPD airway (and contrast with CF), 3) whether acquired CFTR dysfunction increases susceptibility to chronic bacterial infection or respiratory exacerbations in COPD ferrets, and 4) test novel therapies for chronic bronchitis, including advancing CFTR potentiators for this indication. There will be significant synergy between these studies, which will not only employ cutting-edge techniques and animal models but also take advantage of our recognized expertise in leading first-in-class human investigation into CFTR-directed therapies. Noting Dr. Rowe's consistent track record of successes; the innovative, one-of-a-kind capabilities of his laboratory; and the immediate feasibility of proposed objectives, this Program promises to transform the field and uncover treatments that offer momentous improvements to duration and quality of life.