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

项目3 摘要 通常认为，慢性阻塞性肺疾病始于小气道。而一个数字 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更多的了解 我们可以推测，小的CF航空公司的异常也是一样的。 然而，上皮形态、细胞类型和黏膜下缺乏的差异 腺体和连续的软骨表明，小气道并不是简单的“小”。 大型航空公司。对于详细的信息，较小的航空公司相对难以进入 机械学研究。因此，我们对许多关键问题缺乏答案。是什么 慢性阻塞性肺疾病小气道表面液体pH它是如何控制的？什么 将质子分泌到小气道的机制？粘液纤毛运输是否受到干扰 小型航空公司？ASL抗菌剂的活性是否受损？CFTR是否存在于小型呼吸道 足以预防慢性肺病吗？随着慢性肺病的进展，宿主如何 小呼吸道的防御和疾病发生了变化？我们最重要的假设是 小气道中CFTR的缺乏是CF肺疾病发病的关键。 我们将调查3个具体目标： 具体目的1.小气道缺乏CFTR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小气道将是 酸性更强，对宿主的防御能力会有损害。 特定目的2.V-ATPase是否在调节小气道表面中起作用 液体酸碱度？我们假设V-ATPase表达于 小气道上皮细胞的特定细胞类型及其在反馈中的作用 调节ASL pH的机制。 特定目的3.CFTR在小气道中的表达是否会阻止CF猪肺 疾病？我们将使用一种新型的AAV载体在小鼠中选择性地表达CFTR CF型猪的呼吸道上皮细胞。我们将调查CFTR修复的效果 对早期肺部表现的作用。 对这些问题的回答，将指导该领域理解 在小呼吸道疾病和确定更好的治疗CF的策略方面。

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.