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

• 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
• 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

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.

人类远端呼吸道的粘液纤毛先天防御机制 项目总结 呼吸道粘膜纤毛清除(MCC)是维持肺健康的重要先天防御系统。失败 黏液转运在黏液阻塞性肺疾病(MODS)的发病机制中很常见。粘液纤毛 据报道，受纤毛和粘液特性控制的运输(MCT)速率在体内远端呼吸道较慢。 部分反映纤毛变短，纤毛细胞密度降低。粘液浓度是另一个关键参数 确定MCT。然而，将局部纤毛和粘液属性整合到MCT中的机制并不是 明白了。这个问题在小呼吸道(直径2毫米)中尤其重要，因为它们是最早的 霉菌中受影响最大的区域。我们先前的研究表明，强健可减少粘蛋白分泌 CFTR介导的小气道液体分泌，这两种活动都由分泌俱乐部细胞主导，提示 在健康情况下，这种粘液在小气道中的浓度低于近端呼吸道。基础生理学 问题包括：1)为什么小型航空公司表现出较慢的MCT；2)集成的 小气道上皮细胞活性；以及3)黏液浓度较低的较慢的MCT的成本是多少 到小气道区吗？这些问题的答案可能在一定程度上与表面指数下降有关 从远端到近端的呼吸道区域。因此，我们假设粘液的产生和清除 小气道受到严格监管，以实现呼吸道保护和效率之间的平衡 区域内粘液清除。小气道上皮产生一种相对稀薄的粘液，即 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的呼吸道表面积的减少，稀释的粘液 层数和较慢的清除速度也会导致小气道对吸入毒物的易感性增加 地区。为了验证这一中心假设，我们提出了以下目标：1)确定区域和细胞类型- 人类呼吸道中MCT的特定调节机制。我们将确定特定地区的MCC 调节机制，利用人类大小呼吸道细胞和组织外植体培养模型。我们会 然后将区域特定的MCC功能与决定区域特定的气道的表观遗传调节元件相关联 上皮细胞类型，利用多组学方法。2)确定决定远端呼吸道的路径 分泌俱乐部细胞是控制小气道粘液的多维离子/粘蛋白调节细胞 属性。3)找出粘液纤毛先天防御系统失灵的机制 霉菌中的远端呼吸道。我们将测试转录调控的失败是否需要维持远端 气道特异性导致小气道上皮细胞局部MCC功能障碍。我们的首要目标是生成 对区域特定粘毛纤毛先天防御机制的机械论见解，重点是小的 航空公司。我们的目标的实现将为理解正常肺和肺中的MCC提供一个新的范式 如何找到治疗霉菌的新方法。