PPG - Airway Physiology and Pathophysiology in a Porcine CF Model

在CFTR基因鉴定23年后，围绕气道疾病的发病机制仍然存在争议，我们缺乏对许多关键问题的答案，目前的治疗方法不足，囊性纤维化（CF）仍然是一种缩短寿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。CF小鼠不会发生肺疾病，这是大多数CF发病率和死亡率的原因。我们现在已经开发出了CFTR基因靶向改变的猪。CF猪自发地发展CF肺病的标志性特征，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猪不能像野生型猪那样有效地消灭细菌。在这个项目中，三位资深的、高度成就的研究者将抓住这个独特的机会，使用CF猪来回答有关CF肺病的关键问题。这三个项目将共同发现CFTR功能的丧失如何影响：a）粘膜纤毛转运; B）气道对病毒感染的反应; c）HCO 3- 气道表面液体pH的分泌和控制;和d）气道表面上的细菌杀灭。项目负责人在CF中有着出色的合作记录，在这里他们将重点放在共同的目标上。他们的研究具有高度的创造性，并得到了提供创新服务和基础设施的五个核心的支持。PPG的发现将加速为患有这种毁灭性疾病的患者开发新疗法。

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.