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

项目3 摘要 通常认为CF肺病始于小气道。虽然一些 的观察表明这一假设是正确的，我们没有直接的实验 证据因为我们对大型CF中的主机防御缺陷有了更多的了解 我们可以推测小CF气道的异常是相同的。 然而，上皮形态、细胞类型和缺乏粘膜下 腺体和连续的软骨提示小气道不仅仅是“小” 大气道。小气道相对难以进入， 机械研究。因此，我们对许多关键问题缺乏答案。是什么 CF小气道的气道表面液体pH值？如何控制？什么 机制分泌质子进入小气道？粘液纤毛运输是否中断 小气道？ASL抗菌剂的活性是否受损？CFTR在小气道中吗 是否足以预防CF肺病？随着CF肺病的进展， 小气道的防御和疾病会发生变化吗我们的首要假设是 小气道中CFTR的缺乏是CF肺病发病机制的关键。 我们将研究三个具体目标： 具体目标1。小气道CFTR缺乏是否会导致宿主防御缺陷？ 根据我们的初步数据，我们假设新生儿CF小气道将 酸性更强，会损害宿主的防御能力。 具体目标2。V-ATP酶在调节小气道气道表面功能中的作用 液体pH值？我们假设V-ATP酶表达于血管壁的顶端表面， 小气道上皮细胞的特定细胞类型，并在反馈中发挥作用 调节ASL pH的机制。 具体目标3。CFTR在小气道中的表达能否预防CF猪肺 疾病？我们将使用一种新的AAV载体在小细胞中选择性表达CFTR。 CF猪的气道上皮细胞。我们将研究CFTR修复的效果 肺功能早期表现。 对这些问题的回答，将指导该领域理解 小气道疾病和确定更好的治疗CF的策略。

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.