PPG - Airway Physiology and Pathophysiology in a Porcine CF Model

在CFTR基因被发现23年后，关于呼吸道疾病的发病机制仍然存在争议，我们对许多关键问题缺乏答案，现有的治疗方法不足，囊性纤维化(CF)仍然是一种缩短生命且往往致命的疾病。进展的一个主要障碍是缺乏除小鼠以外的CF动物模型。慢性阻塞性肺疾病小鼠不会发展为肺部疾病，这是大多数慢性阻塞性肺疾病发病率和死亡率的原因。我们现在已经培育出了有针对性地改变CFTR基因的猪。慢性阻塞性肺疾病猪会自发地出现慢性阻塞性肺疾病的特征，包括呼吸道感染、炎症、气道壁重塑、粘液堆积和呼吸道阻塞。在出生后的几个小时内，CF猪无法像野猪那样有效地清除细菌。在这个项目中，三位资深的、非常有成就的研究人员将抓住这个独特的机会，使用CF猪来回答关于CF肺部疾病的关键问题。这三个项目将共同发现CFTR功能的丧失如何影响：a)粘液纤毛运输；b)呼吸道对病毒感染的反应；c)HCO3- 呼吸道表面液体pH的分泌和控制；以及d)对呼吸道表面的细菌杀灭。项目负责人在CF方面有着出色的协作记录，在这里他们将重点放在一个共同的目标上。他们的研究具有很高的创造性，并得到提供创新服务和基础设施的五个核心的支持。这种PPG的发现将加速为患有这种毁灭性疾病的患者开发新的治疗方法。

Twenty-three years after identification of the CFTR gene, controversies still surround the pathogenesis of airways disease, we lack answers to many crucial questions, current treatments are inadequate, and cystic fibrosis (CF) remains a life shortening and too often lethal disease. A major impediment to progress has been lack of a CF animal model other than the mouse. CF mice fail to develop lung disease, the cause of most CF morbidity and mortality. We have now 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. In this Program three senior and highly accomplished investigators will seize the unique opportunity to use CF pigs to answer key questions about CF lung disease. Together, the three projects will discover how loss of CFTR function affects: a) mucociliary transport; b) the response of airways to viral infection; c) HCO3- secretion and control of airway surface liquid pH; and d) bacterial killing on the airway surface. The Project Leaders have an outstanding track record of collaboration in CF, and here they sharpen their focus to a common goal. Their research is highly creative and is supported by five cores that provide innovative services and infrastructure. Discoveries from this PPG will accelerate development of novel therapies for patients who suffer from this devastating disease.