Origins of Cystic Fibrosis Airway Disease

囊性纤维化气道疾病的起源

基本信息

批准号：
10470203
负责人：
DAVID A STOLTZ
金额：
$ 229.33万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470203
关键词：
ATP12A gene Address Affect Airway Disease Animal Model Anions Bacteria Bicarbonates Birth Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Defect Development Disease Disease Progression Duct (organ) structure Exhibits Family suidae Genetic Diseases Gland Goals H(+)-K(+)-Exchanging ATPase Host Defense Hour Human Impairment Infection Inflammation Infrastructure Investigation Knowledge Lead Learning Life Link Liquid substance Lung Lung diseases Mediating Methods Morbidity - disease rate Mucociliary Clearance Mucous body substance Newborn Infant Pathogenesis Play Property Proton Pump Proton-Translocating ATPases Protons Pulmonary Cystic Fibrosis Regulator Genes Research Research Personnel Respiratory Failure Respiratory Tract Infections Role Serum Services Site Surface Techniques Virus Diseases airway epithelium airway obstruction airway surface liquid antimicrobial cystic fibrosis airway defined contribution disease phenotype early cystic fibrosis gene discovery injured airway innovation insight mortality novel therapeutic intervention novel therapeutics porcine model prevent programs recurrent infection respiratory success vacuolar H+-ATPase

项目摘要

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.

发现CFTR基因的二十八年，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，我们的疗法是不足，CF仍然是生命的限制，而且常常是致命的疾病。进步的主要障碍缺乏类似于人类的肺部疾病表型的CF动物模型。我们开发了具有CFTR基因的靶向改变的猪。 CF猪自发发展标志 CF肺部疾病的特征，包括气道感染，炎症，气道墙重塑，粘液积累和气道阻塞。出生后的几个小时内，CF猪无法消除细菌有效地为野生型猪。至少有两个宿主防御缺陷，降低了气道抗菌活性表面液体（ASL）和受损的粘膜纤毛运输（MCT）贡献。两者都是由异常酸性气道液体。在这个计划中，三个高度成就的调查人员将使用CF猪回答有关CF肺病的基本问题。这三个项目一起将发现如何 CFTR功能的丧失影响：a）粘膜粘膜函数，粘液的特性和MCT； b）ASL pH和质子分泌通过ATP12A； c）小型气道功能，可能是CF疾病的一个部位发病。项目负责人及其团队拥有协作CF的出色记录研究，在这里，他们将重点放在一个共同的目标上。他们高度创造的研究是由五个提供创新基础设施和服务的核心的支持。通过进一步教育CF 发病机理，它将加速这种致命疾病的新疗法。

项目成果

期刊论文数量（126）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR-/- mice.

具有缩短的 R 结构域的囊性纤维化跨膜电导调节剂可挽救 CFTR-/- 小鼠的肠道表型。

DOI：
10.1073/pnas.1019752108
发表时间：
2011
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Ostedgaard,LyndaS;Meyerholz,DavidK;Vermeer,DanielW;Karp,PhilipH;Schneider,Lindsey;Sigmund,CurtD;Welsh,MichaelJ
通讯作者：
Welsh,MichaelJ

CFTR-deficient pigs display peripheral nervous system defects at birth.

CFTR 缺陷的猪在出生时表现出周围神经系统缺陷。

DOI：
10.1073/pnas.1222729110
发表时间：
2013
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Reznikov,LeahR;Dong,Qian;Chen,Jeng-Haur;Moninger,ThomasO;Park,JungMin;Zhang,Yuzhou;Du,Jianyang;Hildebrand,MichaelS;Smith,RichardJH;Randak,ChristophO;Stoltz,DavidA;Welsh,MichaelJ
通讯作者：
Welsh,MichaelJ

Antibacterial properties of the CFTR potentiator ivacaftor.

DOI：
10.1016/j.jcf.2014.02.004
发表时间：
2014-09
期刊：
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
影响因子：
0
作者：
Reznikov LR;Abou Alaiwa MH;Dohrn CL;Gansemer ND;Diekema DJ;Stoltz DA;Welsh MJ
通讯作者：
Welsh MJ

NETs and CF Lung Disease: Current Status and Future Prospects.

DOI：
10.3390/antibiotics4010062
发表时间：
2015-01-15
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
0
作者：
Gray RD;McCullagh BN;McCray PB
通讯作者：
McCray PB

Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs.

囊性纤维化跨膜电导调节剂增强作为肺水肿的治疗策略：猪的概念验证研究。

DOI：
10.1097/ccm.0000000000002720
发表时间：
2017
期刊：
Critical care medicine
影响因子：
8.8
作者：
Li,Xiaopeng;VargasBuonfiglio,LuisG;Adam,RyanJ;Stoltz,DavidA;Zabner,Joseph;Comellas,AlejandroP
通讯作者：
Comellas,AlejandroP