Mucociliary innate defense mechanism in the human distal airway

人类远端气道的粘液纤毛先天防御机制

基本信息

批准号：
10586404
负责人：
Kenichi Okuda
金额：
$ 58.29万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586404
关键词：
Achievement Affect Air Movements Anatomy Area Asthma Biopsy Specimen Canis familiaris Cell Density Cells Chronic Bronchitis Cilia Coughing Coupled Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Data Reporting Defense Mechanisms Diameter Dimensions Disease Distal Epigenetic Process Epithelial Cells Equilibrium Exhibits Failure Fluids and Secretions Functional disorder Gland Goals Health Homeostasis Human Hydration status Image Inhalation Ion Transport Ions Knowledge Lead Lung Maintenance Mediating Metabolic Clearance Rate Microdissection Modeling Mucins Mucociliary Clearance Mucous body substance Obstruction Pathogenesis Pathology Pathway interactions Physiology Production Property Regulatory Element Reporting Role Sampling Studies Solid Specificity Stress Submucosa Surface System Techniques Testing Tissues Transcriptional Regulation absorption airway epithelium airway surface liquid cell type cost in vivo insight lung health mucus clearance mucus-associated lung diseases multiple omics novel therapeutic intervention prevent pulmonary function regional difference toxicant transcriptome

项目摘要

Mucociliary Innate Defense Mechanism in the Human Distal Airway Project summary Airway mucociliary clearance (MCC) is a critical innate defense system for maintenance of lung health. Failed mucus transport is common to the pathogenesis of muco-obstructive lung diseases (MOLDs). Mucociliary transport (MCT) rates, governed by cilial and mucus properties, are reportedly slower in vivo in distal airways, reflecting in part shorter cilia and reduced ciliary cell density. Mucus concentration is another key parameter that determines MCT. However, mechanisms that integrate regional cilial and mucus properties into MCT are not understood. This question is particularly important in small airways (< 2 mm in diameter), as they are the earliest and most affected region in MOLDs. Our prior studies have demonstrated reduced mucin secretion with robust CFTR-mediated fluid secretion in small airways, both activities dominated by secretory club cells, suggesting that mucus is less concentrated in the small airways relative to proximal airways in health. Basic physiology questions include: 1) why do small airways exhibit slower MCT; 2) how is slower MCT produced by integrated small airway epithelial cellular activities; and 3) what is the cost for the slower MCT with less concentrated mucus to the small airway region? Answers to these questions likely relate in part to the exponential decrease in surface area from distal to proximal airways. Accordingly, we hypothesize that mucus production and clearance in small airways is tightly regulated to achieve a balance between airway protection and efficient intraregional mucus clearance. Small airway epithelia produce a relatively dilute mucus that is transported at relatively slow rates to prevent accumulation in central airways. While this property is necessary to accommodate decrease in surface area from distal to proximal airways, the dilute mucus layer and slower clearance rates also lead to increased vulnerability to inhaled toxicants in small airway regions. To test this central hypothesis, we propose the following aims: 1) Identify region- and cell type- specific regulatory mechanisms for the MCT in human airways. We will identify region-specific MCC regulatory mechanisms, utilizing human large and small airway cell and tissue explant culture models. We will then relate region-specific MCC functions to epigenetic regulatory elements determining region-specific airway epithelial cell types, utilizing multi-omics approaches. 2) Identify pathways determining the distal airway secretory club cell as a multi-dimensional ion/mucin regulatory cell that controls small airway mucus properties. 3) Identify mechanisms that produce failure of mucociliary innate defense systems in the distal airway in MOLDs. We will test whether failure of the transcriptional regulation required to maintain distal airway specificity causes local MCC dysfunction in small airway epithelia. Our overarching goal is to generate mechanistic insights into region-specific mucociliary innate defense mechanisms with a focus on small airways. Achievement of our goal should provide a new paradigm to understand MCC in the normal lung and how to approach novel therapies for MOLDs.

人类远端气道的粘液纤毛先天防御机制项目概要气道粘液纤毛清除（MCC）是维持肺部健康的重要先天防御系统。失败的粘液转运是粘液阻塞性肺病 (MOLD) 发病机制中的常见现象。粘液纤毛据报道，由纤毛和粘液特性控制的转运（MCT）速率在体内远端气道中较慢，部分反映了纤毛较短和睫状细胞密度降低。粘液浓度是另一个关键参数决定MCT。然而，将区域纤毛和粘液特性整合到 MCT 中的机制尚未实现。明白了。这个问题对于小气道（直径 < 2 毫米）尤为重要，因为它们是最早的气道。以及 MOLD 中受影响最严重的区域。我们之前的研究表明，粘蛋白分泌减少，并且具有强大的作用 CFTR 介导的小气道液体分泌，这两种活动均由分泌性俱乐部细胞主导，表明与健康人的近端气道相比，粘液在小气道中的浓度较低。基础生理学问题包括：1）为什么小气道表现出较慢的 MCT； 2）集成产生的MCT如何变慢小气道上皮细胞活动； 3) 粘液浓度较低且速度较慢的 MCT 的成本是多少到小气道区域？这些问题的答案可能部分与表面的指数减少有关从远端气道到近端气道的区域。因此，我们假设粘液的产生和清除小气道受到严格监管，以实现气道保护和高效之间的平衡区域内粘液清除。小气道上皮细胞产生相对稀的粘液，以相对较慢的速度运输，以防止在中央呼吸道积聚。虽然此属性是为了适应从远端到近端气道表面积的减少，稀释的粘液层数和较慢的清除率也导致小气道更容易受到吸入毒物的影响地区。为了检验这一中心假设，我们提出以下目标：1）识别区域和细胞类型人类气道中 MCT 的具体调节机制。我们将确定特定区域的 MCC 调节机制，利用人类大和小气道细胞和组织外植体培养模型。我们将然后将区域特异性 MCC 功能与决定区域特异性气道的表观遗传调控元件联系起来上皮细胞类型，利用多组学方法。 2) 确定确定远端气道的路径分泌俱乐部细胞作为控制小气道粘液的多维离子/粘蛋白调节细胞特性。 3) 确定导致粘膜纤毛先天防御系统失效的机制 MOLD 中的远端气道。我们将测试维持远端所需的转录调控是否失败气道特异性导致小气道上皮局部 MCC 功能障碍。我们的首要目标是产生对特定区域粘液纤毛先天防御机制的机制见解，重点关注小航空公司。我们目标的实现应该为理解正常肺和 MCC 提供一个新的范式。如何寻找针对 MOLD 的新疗法。