Testing the Contributions of Airway Submucosal Glands and Surface Epithelia to Lung Health

测试气道粘膜下腺和表面上皮对肺部健康的贡献

• 批准号: 10597111
• 负责人: DAVID A STOLTZ
• 金额: $ 62.95万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597111
• 关键词: Acceleration; Airway Disease; Animal Model; Asthma; Bacteria; Chronic Obstructive Pulmonary Disease; Cystic Fibrosis; Data; Development; Distal; Epithelium; Exposure to; Family suidae; Foundations; Functional disorder; Future; Genes; Gland; Host Defense; Human; Impairment; Infection; Inflammation; Knowledge; Lung; Lung diseases; MUC5AC gene; MUC5B gene; Mammals; Mediating; Modeling; Mucociliary Clearance; Mucous body substance; Newborn Infant; PET/CT scan; Play; Process; Production; Proteins; Pulmonary Challenge; Regulation; Role; Site; Submucosa; Surface; Techniques; Testing; Time; Virus; airway surface liquid; antimicrobial; antimicrobial peptide; ectodysplasin; gland development; improved; lung health; novel therapeutic intervention; particle; respiratory; respiratory challenge

PROJECT SUMMARY Our lungs are continually exposed to bacteria, viruses, and toxic particles, often complicating common pulmonary disorders such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). To protect the lungs from these challenges, mammals have evolved multiple innate airway defenses that include mucus production, antimicrobial factor secretion, and mucociliary transport (MCT). Both airway submucosal glands (SMG) and surface epithelia contribute to this first line of lung defense. However, the relative importance of their contributions or the interplay between these contributions is not well understood. Furthermore, these defenses depend on maintaining optimal pH and airway surface liquid (ASL) volume. Based on the abundance of SMG and their products, it has been hypothesized that SMG play a critical role in host defense. But that hypothesis has gone untested. We also do not know whether SMG serve host defense under basal conditions or only when they are stimulated to secrete by an airway challenge. Before we can develop novel therapeutic approaches for devastating lung diseases, we must: a) determine the contribution of airway surface epithelia and SMG to airway host defense and b) understand how pH and ASL volume regulate MCT and antimicrobial activity. In this proposal, we focus on the interplay of SMG and surface epithelia. We study pigs because they have airways and SMG like those in humans. We disrupted a gene (EDA) necessary for SMG development. Newborn EDA-KO pigs lack airway SMG, have disrupted MCT, and impaired bacterial killing. Because EDA-KO pigs lack SMG, they provide the exciting opportunity to test our overarching hypothesis that SMG are required for normal airway host defense and that their loss will lead to airway disease. We will test our hypothesis by investigating the following Specific Aims: Aim 1. What is the role of submucosal glands in ASL pH and volume regulation in the airway? Aim 2. How do submucosal glands contribute to large and small airway mucociliary transport? Aim 3. Does decreased antimicrobial peptide- mediated bacterial killing, due to lack of SMG, cause lung disease? Comparing pigs with and without SMG will provide the first direct evidence about whether and how SMG are required for respiratory host defense. The results will also lay a critical foundation for future tests of how SMG contribute to airway disease pathophysiology. Finally, increased scientific knowledge of SMG and interactions between surface epithelia/SMG will provide a better foundation for understanding how ASL is regulated, how MCT is controlled, and ultimately identify desperately needed new targets for lung diseases.

项目概要 我们的肺部不断暴露于细菌、病毒和有毒颗粒中，这常常使常见的疾病变得复杂化。 肺部疾病，例如哮喘、慢性阻塞性肺病（COPD）和囊性纤维化（CF）。 为了保护肺部免受这些挑战，哺乳动物进化出了多种先天呼吸道防御系统 包括粘液产生、抗菌因子分泌和粘液纤毛运输（MCT）。双气道 粘膜下腺 (SMG) 和表面上皮细胞构成了肺的第一道防线。然而， 他们的贡献的相对重要性或这些贡献之间的相互作用尚不清楚。 此外，这些防御取决于维持最佳 pH 值和气道表面液体 (ASL) 体积。 基于 SMG 及其产品的丰富性，推测 SMG 在 主机防御。但这一假设尚未得到检验。我们也不知道 SMG 是否服务于主机防御 在基础条件下或仅当它们受到气道挑战刺激分泌时。在我们可以之前 开发新的治疗方法来治疗毁灭性的肺部疾病，我们必须：a）确定 气道表面上皮和 SMG 与气道宿主防御的关系，以及 b) 了解 pH 和 ASL 容量如何调节 MCT 和抗菌活性。在本提案中，我们重点关注 SMG 和表面上皮细胞的相互作用。我们 研究猪是因为它们有像人类一样的呼吸道和 SMG。我们破坏了必要的基因（EDA） 用于 SMG 开发。新生 EDA-KO 猪缺乏气道 SMG，MCT 被破坏，细菌受损 杀戮。由于 EDA-KO 猪缺乏 SMG，因此它们提供了令人兴奋的机会来测试我们的总体能力 假设 SMG 是正常气道宿主防御所必需的，并且它们的损失将导致气道 疾病。我们将通过调查以下具体目标来检验我们的假设： 目标 1. 的作用是什么 ASL 中粘膜下腺的 pH 值和气道容量调节？目标 2. 粘膜下腺如何 有助于大气道和小气道粘膜纤毛运输？目标 3. 抗菌肽是否减少 由于缺乏 SMG 介导的细菌杀灭，会导致肺部疾病吗？比较使用和未使用 SMG 的猪将 提供了关于呼吸道宿主防御是否以及如何需要 SMG 的第一个直接证据。这 结果还将为未来测试 SMG 如何导致气道疾病奠定重要基础 病理生理学。最后，增加了 SMG 和表面之间相互作用的科学知识 上皮细胞/SMG 将为了解 ASL 如何调节、MCT 如何控制、 并最终确定肺部疾病急需的新靶标。