AIRWAY SUBMUCOSAL GLANDS AND CYSTIC FIBROSIS DISEASE

描述（改编自申请人摘要）：囊性纤维化的死亡率 (CF)通常是由肺部并发症引起的， 包括用粘稠的脱水粘液进行性阻塞气道， 粘液纤毛运输减少、慢性气道感染和支气管扩张。 虽然已知CF是由编码囊性纤维化的基因突变引起的， 纤维化跨膜传导调节蛋白（CFTR），一种cAMP调节的 阴离子通道，该通道功能缺陷与 CF的肺部发病机制尚不清楚且存在争议。使用猪 主要研究者最近表明，CFTR通常 介导气道粘膜下腺体分泌Cl-和HCO 3， 这个过程驱动腺体分泌液体。当腺体分泌液体时 通过应用选择性C1和HCO 3分泌抑制剂，气道 发生与早期CF气道疾病相似的变化--粘液 腺管阻塞，产生异常粘稠的脱水粘液， 和粘膜纤毛运输的减少。根据这些观察，校长 研究者假设CF肺病理学是不可避免的结果 粘膜下腺体Cl-和HCO 3分泌受损。为支持这一 假设，申请人提出以下目的。第一，机制由 哪种腺体液体分泌抑制剂会减少粘液纤毛转运， 测定其次，分泌囊泡在粘液凝胶形成中的作用将 进行研究，以更好地了解粘液成熟的机制和动力学 in airways航空.三、潜在气道促分泌素的疗效及作用机制 将进行评估，以确定可能的CFTR独立路线， 用于治疗性诱导液体分泌。第四，能力 Cl-和HCO 3分泌的抑制剂，以重现 将在分离的灌注肺叶中确定气道。这些拟议 研究将提供重要信息，以了解 腺体Cl-和HCO 3分泌在CF病因中的作用。如果这个假设是 经证实，这些研究可以成为治疗的重要基础 治疗这种致命疾病的策略。

DESCRIPTION(adapted from applicant's abstract): Mortality in cystic fibrosis (CF) typically results from the pulmonary complications of the disease, which include progressive obstruction of the airways with a thick dehydrated mucus, reduced mucociliary transport, chronic airway infections, and bronchiectasis. While CF is known to be caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator protein (CFTR), a cAMP-regulated anion channel, the functional link between defects in this channel function and the pulmonary pathogenesis of CF is unclear and controversial. Using porcine airways, the principal investigator has recently shown that CFTR normally mediates secretion of both Cl- and HCO3 by submucosal glands of the airways and that this process drives secretion of gland liquid. When gland liquid secretion is blocked by applying selective C1- and HCO3 secretion inhibitors, airways undergo changes that parallel those observed in early CF airway disease-- mucus obstruction of gland ducts, production of an abnormally thick dehydrated mucus, and reductions in mucociliary transport. From these observations, the principal investigator hypothesizes that CF lung pathology is the inevitable consequence of impaired Cl- and HCO3 secretion from submucosal glands. In support of this hypothesis, the applicant proposes the following aims. First, the mechanism by which gland liquid secretion inhibitors reduce mucociliary transport will be determined. Second, the role of secretory vesicles in mucus gel formation will be studied to better understand the mechanism and dynamics of mucus maturation in airways. Third, the efficacy and mechanism of potential airway secretogogues will be evaluated to identify possible CFTR-independent routes which could be manipulated for therapeutic induction of liquid secretion. Fourth, the ability of inhibitors of Cl- and HCO3 secretion to reproduce mucus obstruction of airways will be determined in isolated, perfused lung lobes. These proposed studies will provide critical information for understanding the role of glandular Cl- and HCO3 secretion in the etiology of CF. If this hypothesis is confirmed, these studies could form the important basis of therapeutic strategies for the treatment of this lethal disease.