Translational Program in CFTR-Related Airway Diseases

项目摘要/摘要 囊性纤维化跨膜电导调节因子通过以下途径维持上皮功能 在上皮细胞的顶端表面起离子通道的作用，并控制 粘液及其清除。Cftr基因突变可引起慢性萎缩性胃炎，这些突变还 通过改变宿主防御，导致其他呼吸道疾病。我们帮助发现了 在没有先天性突变的情况下，CFTR功能障碍也可以后天获得，从而导致 慢性阻塞性肺疾病慢性支气管炎表型的发病机制 (COPD)。为了达到这一目标，本研究计划将在阐明 与遗传和获得性CFTR功能障碍有关的呼吸道疾病的发病机制，并将 应用这些知识来开发新的诊断和治疗工具。该计划将 包括对NHLBI的使命至关重要的两个重点领域。第一个将解决根本问题 关于粘液清除的问题，使用CF作为模型。我们将在体内实施 μOCT成像，这是我们共同发明的一项技术，提供了前所未有的视角 对呼吸道表面进行功能显微解剖；使用创新技术探查呼吸道 粘液；并使用一种新的CF大鼠，该大鼠表现出粘液清除延迟和 随着时间的推移而发展起来的宿主防御，以1)阐明控制形成的机制 粘液及其清除，2)开发针对异常粘液的新的治疗方法 以及3)建立对慢性细菌易感性增加的机制 感染和根除细菌的新策略。在第二个重点领域，我们将研究 这些通路在慢性支气管炎中的作用，这是一种普遍存在的疾病，缺乏治疗 颠倒它的自然历史。我们将确定1)获得性CFTR功能障碍对 雪貂是第一个慢性支气管炎的动物模型，2)慢性支气管炎黏液淤积的机制 人类慢性阻塞性肺疾病(COPD)(与慢性阻塞性肺疾病对照)，3)获得性CFTR功能障碍是否增加 慢性阻塞性肺病雪貂对慢性细菌感染或呼吸恶化的易感性，以及4) 测试治疗慢性支气管炎的新疗法，包括先进的CFTR增强剂 指示。这些研究之间将产生显著的协同效应，这不仅将使用 尖端技术和动物模型，也利用了我们公认的专业知识 在领导一流的人类对CFTR指导的治疗的研究中。注意到罗医生的 始终如一的成功记录；他的实验室独一无二的创新能力； 和拟议目标的直接可行性，该计划承诺将转变 现场和发现治疗，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.