Contribution of Small Airways to Mucociliary Transport Dysfunction

小气道对粘膜纤毛运输功能障碍的影响

• 批准号: 10659465
• 负责人: Mahmoud Abou Alaiwa
• 金额: $ 71.08万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659465
• 关键词: Affect; Air; Airway Disease; Algorithmic Analysis; Alveolar; Animal Model; Anions; Asthma; Back; Biological Assay; Biological Models; Birth; Blood; Characteristics; Chronic Obstructive Pulmonary Disease; Cilia; Clinical; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Development; Disease model; Distal; Duct (organ) structure; Early Intervention; Elasticity; Environment; Event; Family suidae; Functional disorder; Gases; Genetic Transcription; Gland; Goals; Host Defense Mechanism; Impairment; Individual; Inhalation; Invaded; Liquid substance; Locomotion; Lung; Lung diseases; Measures; Mediating; Microbe; Motion; Movement; Mucociliary Clearance; Mucolytics; Mucous body substance; Organism; Outcome; Outcome Study; Oxygen; PET/CT scan; Particle Size; Pathogenesis; Periodicals; Positron; Positron-Emission Tomography; Primary Ciliary Dyskinesias; Process; Property; Research; Role; Signal Transduction; Slice; Submucosa; Surface; System; Techniques; Testing; Therapeutic; Time; Trachea; Transgenic Animals; Tube; airway epithelium; children with cystic fibrosis; cystic fibrosis airway; digital; idiopathic pulmonary fibrosis; in vivo; innovation; model organism; novel; novel strategies; novel therapeutic intervention; novel therapeutics; particle; pathogen; preference; prevent; radiotracer; success; temporal measurement; tris(2-carboxyethyl)phosphine; viscoelasticity

PROJECT SUMMARY The airway system is composed of asymmetric dichotomously branching tubes lined with respiratory epithelium that form a barrier at the interface with the environment. The airways carry a simple function of conducting oxygen rich air to the alveolar space where gas exchange with the blood occur. By doing that, pathogens and particles enter the lungs. Mucociliary transport is a host defense mechanism that protect the lungs from invading organisms. Defects in mucociliary transport contributes to many airway diseases such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, and primary ciliary dyskinesia. We developed limited understanding of the mechanism of MCT in large airways by investigating the role of submucosal gland secretions. We found that mucus strands secreted by submucosal glands are critical to initiate movement of large particles in large airways. We also found that in CF airways, due to loss of CFTR-mediated anion secretion, mucus strands are abnormally elastic. They fail to detach from submucosal gland duct opening and often recoil backward while transporting on the airway surface. Small airways constitute the majority of the surface airway of the lungs and it is suggested that may contribute to some of the abnormalities seen in several airway diseases. The hypothesis that mucociliary defects in small airways contribute to CF airway disease pathogenesis has largely remained untested. In addition, the characteristic features of MCT in small airways has remained poorly understood. To understand mucociliary transport in the small airways, we developed a positron emission based mucociliary transport assay with high spatial and temporal resolution not achieved before. We used CF airway disease as a disease model of impaired mucociliary transport. To realize our overarching goal of understanding the mechanism of mucociliary transport in both small and large airways, we will test hypotheses in the following Specific Aims: Aim 1. What is the mechanism of metachronal motion in vivo? Does disruption of mucus viscoelastic properties alter metachronal motion? Does loss of submucosal gland mucus secretion affect metachronal motion? Is metachronal motion impaired in CF airways? Aim 2. Is mucociliary clearance defective in CF small airways? Does loss of CFTR cause an MCC defect? Will HEMT correct it? Will an inhaled mucolytic (TCEP) correct it? Aim 3. Is early intervention (at birth) sufficient to prevent/delay CF airway disease? Does HEMT revert CF airway disease back to normal in young piglets? Are mucolytics effective as a bridge therapy until HEMT are initiated? The results are very important in understanding the mechanism of MCT and how MCT is controlled, and ultimately identify desperately new targets for lung diseases. The results will also guide development of newer therapeutics or combination of therapeutics.

项目摘要 气道系统由不对称的二歧管组成，其上覆有呼吸上皮 在与环境的界面上形成了一个屏障。气道的功能很简单， 富氧空气进入肺泡空间，在那里与血液进行气体交换。通过这样做，病原体和 颗粒进入肺部。粘膜纤毛转运是一种宿主防御机制，保护肺免受 入侵生物粘液纤毛运输的缺陷导致许多气道疾病，如哮喘， 慢性阻塞性肺疾病、特发性肺纤维化、囊性纤维化和原发性睫状 运动障碍我们通过研究大气道中MCT的机制， 粘膜下腺体分泌物的作用。我们发现粘膜下腺体分泌的粘液链 这对于启动大颗粒在大气道中的运动至关重要。我们还发现，在CF气道中，由于 CFTR介导的阴离子分泌，粘液链异常弹性。它们无法从粘膜下层分离 腺管开放，在气道表面运输时经常向后反冲。小气道 构成肺的表面气道的大部分，并且建议可能有助于一些 在几种气道疾病中观察到的异常。小气道黏膜纤毛缺陷的假说 导致CF气道疾病的发病机制在很大程度上仍然未经检验。此外， 小气道中MCT的特征仍然知之甚少。为了了解粘膜纤毛的运输， 小气道，我们开发了一种基于正电子发射的粘液纤毛转运试验， 时间分辨率以前没有达到。我们使用CF气道疾病作为受损的 粘液纤毛运输为了实现我们的首要目标，了解粘膜纤毛的机制， 在小型和大型航空公司的运输，我们将测试假设在以下具体目标：目标1。什么 是体内异时运动的机制吗？粘液粘弹性的破坏是否改变了 异时运动粘膜下腺体粘液分泌的减少是否影响异时运动？是 CF气道的异时性运动受损？目标2.小CF的粘膜纤毛清除功能是否有缺陷 航空？CFTR丢失是否会导致MCC缺陷？HEMT会纠正吗？吸入粘液溶解剂（TCEP） 纠正吗？目标3.早期干预（出生时）是否足以预防/延迟CF气道疾病？并 HEMT可使幼猪CF气道疾病恢复正常？粘液溶解剂作为桥梁治疗有效吗 直到HEMT启动这一结果对于了解MCT的作用机制以及如何在体内发挥作用具有重要意义。 MCT是受控的，并最终确定了肺部疾病的新靶点。结果也将指导 开发新的治疗剂或治疗剂的组合。