Early airway infection in a porcne model of cystic fibrosis

囊性纤维化猪模型的早期气道感染

• 批准号: 7486390
• 负责人: Joseph Zabner
• 金额: $ 28.81万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486390
• 关键词: Age; Air; Animal Model; Area; Arts; Bacteria; Caliber; Chronic; Clinical Research; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease; Disruption; Dose; Family suidae; Future; Genes; Human; Imaging Techniques; Infection; Knowledge; Lead; Longevity; Lung; Lung diseases; Maxillary Sinus; Modeling; Morbidity - disease rate; Mucociliary Clearance; Mus; Nasopharynx; Particle Size; Pathogenesis; Phagocytes; Phagosomes; Phenotype; Play; Pseudomonas aeruginosa; Pulmonary Cystic Fibrosis; Relative (related person); Research; Research Personnel; Role; Serological; Staphylococcus aureus; Sterility; Structure; Sus scrofa; Thiocyanates; Time; Viral; Virus Diseases; airway obstruction; antimicrobial; base; cystic fibrosis airway; cystic fibrosis mouse; cystic fibrosis patients; hypothiocyanite; macrophage; microorganism; mortality; neutrophil; novel; pathogen; postnatal; pulmonary function decline; respiratory; response; thiocyanate

Loss of the cystic fibrosis transmembrane conductance regulator (CFTR) causes lung disease that is the major cause of morbidity and mortality in people with cystic fibrosis (CF). Yet despite outstanding progress in several areas of basic, translational and clinical research, we still do not know why do CF lungs become colonized with bacteria. On the basis of combined culture and serologic results, over 97% of patients with CF are infected with P. aeruginosa by the age of 3. Infection with P. aeruginosa is associated with pulmonary function decline and early mortality. Most current research on P. aeruginosa in patients with CF focuses on chronic infection. Knowledge of the mechanisms that allow the initial colonization of the CF airways is limited by the difficulty of clinical research, technical problems and ethical considerations. Although CF mice have been developed, during their limited lifespan they do not develop the airway disease typically found in humans. A major impediment to studying airway colonization with bacteria is the lack of an animal model (non-murine) that replicates the lung disease in humans with CF. We generated pigs with disruption of the CFTR gene. We decided to study pigs because their lungs are very similar to humans. If the CFTR-null pigs are colonized with P. aeruginosa or any other bacteria, it will be an extremely exiting discovery. It will provide an animal model that will allow investigators to fully describe mechanistically the pathogenesis of CF lung infections, in particular at the earliest period: the initial colonization of the CF airways. Our overarching hypothesis is that lack of CFTR will result in bacterial airway colonization in pig airways. We propose 3 specific aims. Specific Aim 1: CFTR null pigs are susceptible to bacteria and viral colonization. This aim will be critical in establishing how the CF lung and environmentally encountered microorganisms interact and lead to the CF phenotype. We will also determine whether CF pigs develop airway obstruction. Specific Aim 2: The airways of CFTR null pigs can be experimentally colonized by CF bacterial pathogens. Challenging the airways with bacteria that infect human CF lungs and with porcine respiratory bacterial pathogens will allow us to investigate the early pathogenesis of disease, elucidate the response to infection, and provide models for many future studies. Specific Aim 3: Lack of CFTR in pig results in abnormal mucociliary clearance, defective antimicrobial activity, and/or altered phagocyte function of macrophages. We will investigate if CFTR plays a role in each one of these antimicrobial mechanisms in pigs. We will investigate the ability of pig CF airways to clean bacterial-sized particles, transport thiocyanate, generate hypothiocyanite, and the acidification of phagosomes in both pig neutrophils and macrophages.

囊性纤维化跨膜电导调节剂（CFTR）的丧失导致肺部疾病 囊性纤维化患者（CF）的发病率和死亡率的主要原因。尽管取得了出色的进步 基本，转化和临床研究的几个领域，我们仍然不知道为什么CF肺会变成 用细菌定植。根据培养和血清学结果的结合，超过97％的患者 CF在3岁时被铜绿假单胞菌感染。铜绿假单胞菌感染与肺部有关 功能下降和早期死亡率。目前对铜绿假单胞菌的大多数CF患者的研究都集中在 慢性感染。了解允许CF气道初始定殖的机制有限 由于临床研究，技术问题和道德考虑的困难。虽然CF小鼠有 已开发，在寿命有限的情况下，他们没有发展出通常发现的气道疾病 人类。用细菌研究气道定植的主要障碍是缺乏动物模型 （非疗法）复制人类的肺部病。我们产生了猪的中断 CFTR基因。我们决定研究猪，因为它们的肺与人类非常相似。如果CFTR无效猪 用铜绿假单胞菌或任何其他细菌殖民，这将是一个极其退出的发现。会 提供一个动物模型，该模型将使研究人员能够完全描述CF的发病机理 肺部感染，特别是在最早的时期：CF气道的初始定植。我们的总体 假设是缺乏CFTR会导致猪气道中的细菌气道定植。我们提出3 具体目标。 具体目标1：CFTR无效猪容易受到细菌和病毒定殖的影响。这个目标至关重要 建立CF肺和环境遇到的微生物如何相互作用并导致CF 表型。我们还将确定CF猪是否会出现气道阻塞。 具体目标2：CFTR无效猪的气道可以通过CF细菌病原体实验定植。 通过感染人类CF肺和猪呼吸细菌的细菌来挑战气道 病原体将使我们能够研究疾病的早期发病机理，阐明对感染的反应， 并为许多未来的研究提供模型。 特定目的3：猪缺乏CFTR会导致粘膜纤毛清除异常，有缺陷的抗菌素 巨噬细胞的活性和/或改变的吞噬细胞功能。我们将调查CFTR是否在每个中发挥作用 猪中的这些抗菌机制之一。我们将研究猪CF气道清洁的能力 细菌大小的颗粒，转运硫氰酸盐，产生下氨酸盐和酸化 猪中性粒细胞和巨噬细胞中的吞噬体。