Project 2: Contribution of a Non-Gastric Proton Pump to Airway Acidification, Respiratory Host Defense, and Lung Disease in Cystic Fibrosis

项目2 项目摘要/摘要 CFTR阴离子通道的缺失会导致囊性纤维化(CF)，其特征是细菌感染和 发炎。为了了解慢性阻塞性肺疾病是如何破坏呼吸道防御的，我们培育了慢性阻塞性肺疾病猪，并发现在 在它们出生的那一天，它们的呼吸道宿主防御系统就受到了损害。在几周内，它们会自发形成 CF呼吸道的特征：感染、炎症、重塑、粘液堆积和阻塞。的研究 Cf猪暴露出至少两个呼吸道宿主防御缺陷：呼吸道中抗菌素活性降低 表面液体和粘液纤毛运输受损。这两种缺陷至少部分是由一种不正常的 酸性呼吸道液体。CFTR介导的碳酸氢盐分泌丧失使酸分泌不受抑制， 降低PH值。我们发现，质子泵(ATP12A)负责将酸分泌到呼吸道中。这个 该项目的主要目标是了解ATP12A酸分泌如何损害宿主防御以及是否 酸性酸碱会引起慢性阻塞性肺疾病。该项目解决了三个主要问题。首先，ATP12A怎么样了？ CF呼吸道的胃酸分泌受调节吗？了解ATP12A的控制很重要，因为 H+分泌的速度会改变pH，这可能会加剧或减轻疾病的严重程度。第二件事是什么 粘膜下腺管腔内的pH值？粘膜下腺产生大部分呼吸道粘液。早些时候 研究表明，从CF粘膜下腺导管中冒出的粘液有时无法从粘膜下导管中分离出来 导管，这损害了粘液纤毛的运输。那些发现和认识到酸性酸碱值会增加 粘液弹性使得了解粘膜下腺腔内的PH值是非常必要的。这项建议是根据 获取这些信息的新方法。第三，扰乱ATP12A基因能挽救CF缺陷吗？Cf猪 ATP12A基因被破坏，将允许对阻止胃酸分泌将 提高粘膜下腺管腔的pH值，改善粘液纤毛运输，预防慢性阻塞性肺疾病。这 研究将使我们能够更好地了解CF如何改变粘膜下腺腔和呼吸道的PH值 表面，从而扰乱呼吸道宿主的防御。对CF发病机制的认识将会加快 发现治疗这种致命疾病的新疗法和疗法。

PROJECT 2 PROJECT SUMMARY/ABSTRACT Loss of the CFTR anion channel causes cystic fibrosis (CF), which is characterized by bacterial infection and inflammation. To understand how CF disrupts airway defenses, we generated CF pigs and found that on the day they are born, they have impaired respiratory host defenses. Within weeks, they spontaneously develop hallmarks of CF airways: infection, inflammation, remodeling, mucus accumulation, and obstruction. Studies of CF pigs revealed at least two respiratory host defense defects: reduced activity of antimicrobials in airway surface liquid and impaired mucociliary transport. Both defects are caused, at least in part, by an abnormally acidic airway liquid. Loss of CFTR-mediated bicarbonate secretion leaves unchecked acid secretion that reduces pH. We found that a proton pump (ATP12A) is responsible for secreting acid into the airways. The overarching goal of this project is to understand how ATP12A acid secretion impairs host defense and whether the acidic pH causes CF lung disease. The project addresses three main questions. First, how is ATP12A acid secretion regulated in CF airways? Understanding the control of ATP12A is important because varying the rate of H+ secretion will change pH, which could exacerbate or attenuate disease severity. Second what is the pH in the lumen of submucosal glands? Submucosal glands produce most of the airway mucus. Earlier work showed that mucus emerging from CF submucosal glands ducts sometimes failed to break free from the duct, which impaired mucociliary transport. Those discoveries and knowledge that an acidic pH increases mucus elasticity make it imperative to know the pH in the submucosal gland lumen. This proposal develops novel means to obtain that information. Third, does disrupting the ATP12A gene rescue CF defects? CF pigs that have a disrupted ATP12A gene will allow a test of the hypotheses that preventing acid secretion will increase pH in the submucosal gland lumen, improve mucociliary transport, and prevent CF lung disease. This research will allow us to better understand how CF alters pH in the submucosal gland lumen and at the airway surface, thereby disrupting respiratory host defenses. The knowledge of CF pathogenesis will accelerate discovery of novel therapies and cures for this lethal disease.