Airway Submucosal Glands and Cystic Fibrosis Disease

气道粘膜下腺和囊性纤维化疾病

• 批准号: 7226986
• 负责人: STEPHEN T BALLARD
• 金额: $ 27.69万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-10 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226986
• 关键词: Adenylate Cyclase; Affect; Anions; Autologous; Bacterial Infections; Biology; Bronchi; Bronchiectasis; Cessation of life; Chronic; Class; Clinic; Code; Cyclic AMP; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Defect; Development; Disabled Persons; Disease; Disruption; Distal; Duct (organ) structure; Elements; Environment; Etiology; Event; Family suidae; Flushing; Future; Gel; Genes; Gland; Growth; Guanylate Cyclase; Human; In Vitro; Indium; Lead; Liquid substance; Lung; Lung diseases; Measures; Mediating; Modeling; Mucociliary Clearance; Mucous Membrane; Mucous body substance; Mutation; Oxygen measurement, partial pressure, arterial; Pathogenesis; Pathology; Pathway interactions; Pattern; Phospholipase C; Physiological; Process; Production; Pseudomonas aeruginosa; Publishing; Research; Role; Role playing therapy; Series; Signal Pathway; Signal Transduction; Surface; Sus scrofa; Techniques; Thick; Tissues; Trachea; Tracheobronchial; Transfection; Transplant Recipients; Transplantation; Uncertainty; body system; cystic fibrosis airway; cystic fibrosis patients; early cystic fibrosis; inhibitor/antagonist; macromolecule; neutrophil; pathogenic bacteria; regional difference; research study; response; small hairpin RNA; therapeutic target

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is caused by deleterious mutations in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated anion channel. Numerous organ systems are affected in CF, but death typically results from the lung disease which is typified by the production of unusually thick mucus, severe chronic bacterial infections, and bronchiectasis. Unfortunately, the underlying sequence of events which leads to this pattern of pathology is unclear and controversial. Our longstanding hypothesis is that CFTR mediates liquid secretion by tracheobronchial submucosal glands which is important for hydrating the macromolecular component of gland secretion and flushing this material through the gland ducts to the airway surface. Thereby, in CF, loss of CFTR function would lead to secretion of overly thick mucus from glands and depletion of periciliary fluid at the airway surface. Disruption of mucociliary transport thus occurs, predisposing the airways to bacterial colonization. Our previous studies of pig airways demonstrated that inhibition of anion and liquid secretion reproduces much of the lung pathology of CF including mucus occlusion of submucosal glands, secretion of inspissated mucus, depletion of periciliary fluid, and impaired mucociliary transport. With the present application, we propose a series of studies which we anticipate will strengthen this hypothesis. Using pig airways as a model, we will define critical aspects of the intracellular signal transduction elements for physiologically important endogenous secretogogues that will help define how secretion is regulated, clarify the role played by CFTR, and identify possible targets for therapeutic manipulation. We will obtain and study human CF airways to document which gland secretion pathways are disabled or intact in this disease. We will pursue development of an in vitro technique to model CF in porcine airways by utilizing shRNA to reduce CFTR expression in explants of airway tissue. Using anion and liquid secretion inhibitors to model the CF defect in pigs airways, we will examine the consequences of thick mucus on Pseudomonas aeruginosa colonization of the airway mucosa. We believe that these studies will provide crucial new information regarding the role of airway glands in the pulmonary pathogenesis of CF airway disease. Without doubt, development of future treatment strategies for CF will depend upon a better understanding of the underlying causes of the disease process.

描述（由申请人提供）：囊性纤维化（CF）是由编码囊性纤维化跨膜传导调节因子（CFTR）（cAMP激活的阴离子通道）的基因中的有害突变引起的。CF中许多器官系统受到影响，但死亡通常由肺部疾病引起，其典型特征是产生异常粘稠的粘液，严重的慢性细菌感染和支气管扩张。不幸的是，导致这种病理模式的潜在事件顺序尚不清楚，也存在争议。我们长期以来的假设是CFTR介导气管支气管粘膜下腺体的液体分泌，这对于使腺体分泌物的大分子组分水合并将该物质通过腺管冲洗到气道表面是重要的。因此，在CF中，CFTR功能的丧失将导致腺体分泌过厚的粘液和气道表面处的纤毛周围液的消耗。因此发生粘膜纤毛运输的破坏，使气道易于细菌定植。我们以前对猪气道的研究表明，抑制阴离子和液体分泌重现了CF的许多肺病理学，包括粘膜下腺体的粘液闭塞、粘液分泌、纤毛周液消耗和粘膜纤毛转运受损。在本申请中，我们提出了一系列研究，我们预计将加强这一假设。使用猪气道作为模型，我们将定义生理上重要的内源性促分泌素的细胞内信号转导元件的关键方面，这将有助于定义分泌是如何调节的，澄清CFTR所起的作用，并确定治疗操作的可能靶点。我们将获得并研究人类CF气道，以记录在这种疾病中哪些腺体分泌途径被禁用或完好。我们将致力于开发一种体外技术，通过利用shRNA减少气道组织外植体中CFTR的表达来模拟猪气道中的CF。使用阴离子和液体分泌抑制剂来模拟猪气道中的CF缺陷，我们将检查厚粘液对铜绿假单胞菌在气道粘膜中定殖的后果。我们相信，这些研究将提供重要的新信息，气道腺体的作用，在肺发病机制的CF气道疾病。毫无疑问，CF未来治疗策略的发展将取决于对疾病过程的根本原因的更好理解。