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.

项目总结 我们的肺部不断地暴露在细菌、病毒和有毒颗粒中，这往往会使常见的 肺部疾病，如哮喘、慢性阻塞性肺疾病(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的呼吸道防御系统 包括粘液产生、抗菌因子分泌和粘液纤毛运输(MCT)。两个呼吸道 粘膜下腺(SMG)和表面上皮细胞构成了这一第一道肺防线。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还没有得到很好的理解。 此外，这些防御依赖于维持最佳的pH值和呼吸道表面液体(ASL)量。 根据SMG及其产品的丰富程度，已经假设SMG在 主场防守。但这一假设尚未得到检验。我们也不知道SMG是否服务于东道主防守 在基础条件下或仅当它们被呼吸道刺激分泌时。在我们可以 在为毁灭性的肺部疾病开发新的治疗方法时，我们必须：a)确定 呼吸道表面上皮细胞和SMG对呼吸道宿主防御和b)了解pH和ASL容量如何调节 MCT和抗菌活性。在这个方案中，我们关注SMG和表面上皮细胞的相互作用。我们 研究猪是因为它们和人类一样有呼吸道和SMG。我们打乱了一种必需的基因(EDA) 用于SMG开发。新生的EDA-KO猪缺乏呼吸道SMG，MCT紊乱，细菌受损 杀戮。因为EDA-KO猪缺乏SMG，它们提供了令人兴奋的机会来测试我们的总体 假设SMG是正常的呼吸道宿主防御所必需的，并且它们的丢失将导致呼吸道 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. 粘膜下腺在ASL中的pH值和气道容量调节？目的2.粘膜下腺如何 对大小呼吸道粘液纤毛运输有贡献吗？目的3.减少抗菌肽- 介导的细菌杀灭，由于缺乏SMG而导致肺部疾病？对比添加和不添加SMG的猪将 提供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。这个 这些结果也将为未来SMG如何促进呼吸道疾病的测试奠定关键基础 病理生理学。最后，增加了对SMG和表面之间相互作用的科学知识 上皮细胞/SMG将为理解ASL是如何调节的，MCT是如何控制的， 并最终确定迫切需要的肺部疾病新靶点。