Origins of Cystic Fibrosis Airway Disease

在发现CFTR基因28年后，囊性纤维化(CF)的呼吸道病因 疾病仍然存在争议，我们仍然缺乏对许多关键问题的答案，我们的治疗方法是 不充分，而且CF仍然是一种限制生命的疾病，而且往往是致命的。进步的主要障碍 一直缺乏具有类似于人类CF的肺部疾病表型的CF动物模型。我们 培育出了CFTR基因靶向改变的猪。Cf猪自发地形成这种标志 慢性阻塞性肺疾病的特点，包括呼吸道感染、炎症、气道壁重构、粘液 积聚和呼吸道阻塞。在出生的几个小时内，CF猪无法清除细菌，因为 实际上就像野猪一样。至少两个宿主防御缺陷，降低了呼吸道的抗菌活性 体表液体(ASL)和粘液纤毛转运受损(MCT)起作用。两者都是由 反常的酸性呼吸道液体。在这个项目中，三名非常有成就的研究人员将使用CF猪 回答有关慢性肺病的基本问题。这三个项目将共同发现如何 CFTR功能丧失影响：a)粘膜下腺功能、粘液特性和MCT；b)ASL PH和通过ATP12A的质子分泌；以及，c)小气道功能，可能是CF病的一个部位 发病机制。项目负责人及其团队在协作配置文件方面有着出色的记录 研究，在这里，他们将重点放在一个共同的目标上。他们极具创造性的研究是 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 从发病机制上讲，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.