Project 3: Contribution of Small Airways to Cystic Fibrosis Lung Disease Pathogenesis

项目 3：小气道对囊性纤维化肺病发病机制的贡献

• 批准号: 10470212
• 负责人: Joseph Zabner
• 金额: $ 35.69万
• 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: 2008-09-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470212
• 关键词: ATP12A gene; Affect; Air; Airway Disease; Apical; Cartilage; Clinical; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Disease; Epithelial; Epithelial Cells; Family suidae; Feedback; Gene Expression Profile; Gland; Host Defense; Immune; Impairment; Inflammation; Knowledge; Lung; Lung diseases; Morphology; Mucociliary Clearance; Mucous body substance; Natural Immunity; Newborn Infant; Pathogenesis; Physiology; Play; Protein Isoforms; Proton-Translocating ATPases; Protons; Pulmonary Cystic Fibrosis; Regulation; Role; Surface; Viral Respiratory Tract Infection; Virus; adeno-associated viral vector; airway epithelium; airway surface liquid; antimicrobial; base; cell type; cystic fibrosis airway; early cystic fibrosis; intervention effect; novel; prevent; restoration; selective expression; vacuolar H+-ATPase; vector

PROJECT 3 ABSTRACT It is often assumed that CF lung disease begins in the small airways. While a number of observations suggest this assumption is correct, we do not have direct experimental evidence. Because we have more knowledge of host defense defects in large CF airways, we might conjecture that the abnormalities in small CF airways are the same. However, differences in epithelial morphology, cell types, and lack of submucosal glands and continuous cartilages suggest that small airways are not simply “small” large airways. The small airways have been relatively inaccessible for detailed mechanistic studies. As a result, we lack answers to many key questions. What is the airway surface liquid pH in CF small airways? How is it controlled? What mechanism secretes protons into small airways? Is mucociliary transport disrupted in small airways? Is the activity of ASL antimicrobials impaired? Is CFTR in small airways sufficient to prevent CF lung disease? As CF lung disease progresses how do host defenses and disease in small airways change? Our overarching hypothesis is that lack of CFTR in the small airway is pivotal for the pathogenesis of CF lung disease. We will investigate 3 specific aims: Specific Aim 1. Does lack of CFTR in small airways result in host defense defects? Based on our preliminary data we hypothesize that newborn CF small airways will be more acidic, and will have an impairment in host defenses. Specific Aim 2. Does V-ATPase play a role in regulating small airways airway surface liquid pH? We hypothesize that V-ATPase is expressed on the apical surface of a specific cell type of small airway epithelial cells and plays a role in a feedback mechanism that regulates ASL pH. Specific Aim 3. Will CFTR expression in small airways of prevent CF pig lung disease? We will use a novel AAV vector to selectively express CFTR in the small airway epithelial cells of CF pigs. We will investigate the effect of restoration of CFTR function on manifestations of early lung. Answers to these questions, will guide the field in understanding the contribution of small airways to disease and in identifying strategies for better treatments of CF.

项目3 抽象的 通常认为CF肺部疾病始于小气道。而一个数字 观察结果表明此假设是正确的，我们没有直接的实验 证据。因为我们对大CF中的宿主防御缺陷有更多的了解 航空公司，我们可能会猜想小CF气道的异常情况是相同的。 但是，上皮形态，细胞类型和缺乏粘膜的差异 腺体和连续软骨表明，小气道不仅是“小” 大气道。小气道相对无法访问 机械研究。结果，我们缺乏许多关键问题的答案。是什么 CF小气道中的气道表面液体pH？如何控制？什么 机制将质子分泌到小气道中？粘毛运输中断 小气道？ ASL抗菌剂的活性是否受损？在小气道中CFTR 足以预防CF肺部疾病？随着CF肺病的发展，宿主如何 小气道的防御和疾病发生变化吗？我们的总体假设是 小气道缺乏CFTR对于CF肺部疾病的发病机理至关重要。 我们将研究3个具体目标： 特定的目标1。在小气道中缺乏CFTR会导致宿主防御缺陷吗？ 根据我们的初步数据，我们假设新生儿CF小气道将是 更酸性，并将在宿主防御措施中受到损害。 特定的目标2。v-atpase在调节小气道表面中起作用 液体pH？我们假设V-ATPase在A的顶表面表达 小气道上皮细胞的特定细胞类型，并在反馈中起作用 调节ASL pH的机制。 特定的目标3。将在预防CF猪肺的小气道中表达CFTR 疾病？我们将使用新颖的AAV矢量选择性地表达小型CFTR CF猪的气道上皮细胞。我们将研究CFTR恢复的效果 在早期肺的表现上起作用。 这些问题的答案将指导该领域了解 小型气道通往疾病，并确定更好地治疗CF的策略。