Origins of Cystic Fibrosis Airway Disease

发现CFTR基因28年后，囊性纤维化（CF）气道的原因 疾病仍然存在争议，我们仍然缺乏许多关键问题的答案，我们的治疗方法是 CF仍然是一种限制生命的疾病，而且往往是致命的疾病。进步的主要障碍 缺乏具有与患有CF的人类相似的肺病表型的CF动物模型。我们 培育出CFTR基因有针对性改变的猪。CF猪会自发地发展出 CF肺病的特征，包括气道感染、炎症、气道壁重塑、粘液 积聚和气道阻塞。在出生后的几个小时内，CF猪无法根除细菌， 与野生型猪一样。至少两种宿主防御缺陷，气道抗菌活性降低 表面液体（ASL）和受损的粘膜纤毛转运（MCT）起作用。两者都是由 异常酸性的气道液体。在这个项目中，三位非常有成就的研究人员将使用CF猪 来回答有关CF肺病的基本问题。这三个项目将共同探索 CFTR功能丧失影响：a）粘膜下腺体功能、粘液性质和MCT; B）ASL 通过ATP 12 A的pH和质子分泌;以及c）小气道功能，CF疾病的可能部位 发病机制项目负责人及其团队在协作CF方面有着出色的记录 研究，在这里，他们把注意力集中在一个共同的目标上。他们极具创造性的研究 由提供创新基础设施和服务的五个核心提供支持。通过进一步教育CF 它将加速发现这种致命疾病的新疗法。

Twenty-eight years after the discovery of the CFTR gene, the causes of cystic fibrosis (CF) airway disease remain controversial, we still lack answers to many critical questions, our therapies are inadequate, and CF remains a life limiting and too often lethal disease. A major impediment to progress has been lack of CF animal models with a lung disease phenotype resembling humans with CF. We developed pigs with targeted alterations of the CFTR gene. CF pigs spontaneously develop the hallmark features of CF lung disease, including airway infection, inflammation, airway wall remodeling, mucus accumulation, and airway obstruction. Within hours of birth, CF pigs fail to eradicate bacteria as effectively as wild-type pigs. At least two host defense defects, reduced antimicrobial activity in airway surface liquid (ASL) and impaired mucociliary transport (MCT) contribute. Both were caused by abnormally acidic airway liquid. In this Program three highly accomplished investigators will use CF pigs to answer fundamental questions about CF lung disease. Together, the three projects will discover how loss of CFTR function affects: a) submucosal gland function, the properties of mucus, and MCT; b) ASL pH and proton secretion via ATP12A; and, c) small airways function, a likely site of CF disease pathogenesis. The Project Leaders and their teams have an outstanding track record of collaborative CF research, and here they sharpen their focus to a common goal. Their highly creative research is supported by five cores that provide innovative infrastructure and services. By further educating CF pathogenesis, it will accelerate discovery of novel therapies for this lethal disease.