Contribution of pulmonary ionocytes and neuroendocrine cells to ion transport-mediated airway surface liquid maintenance

肺离子细胞和神经内分泌细胞对离子转运介导的气道表面液体维持的贡献

• 批准号: 10456654
• 负责人: Preston E Bratcher
• 金额: $ 49.91万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-25 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456654
• 关键词: Active Ion Transport; Affect; Airway Disease; Airway Resistance; Animals; Asthma; CRISPR/Cas technology; Cell Count; Cells; Chronic; Chronic Obstructive Pulmonary Disease; Cilia; Communication; Complex; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Disease; Disease model; Enterobacteria phage P1 Cre recombinase; Epithelial; Epithelial Cells; Equilibrium; Exons; Frequencies; Functional disorder; Future; Gene Mutation; Health; Human; Immunofluorescence Immunologic; Immunohistochemistry; Impairment; Individual; Inherited; Ion Channel; Ion Transport; Ions; Irritants; Knock-out; Liquid substance; Lung; Lung Compliance; Maintenance; Measures; Mediating; Methods; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Mus; Mutation; Nasal Epithelium; Neuroendocrine Cell; Nose; Passive Ion Transport; Play; Process; Property; Regulation; Research; Respiration Disorders; Respiratory System; Rest; Role; Severity of illness; Signal Transduction; Site; Stimulus; Structure; Surface; Techniques; Technology; Time; Tissues; Tracheal Epithelium; Transcript; Upper respiratory tract; Viscosity; Water Movements; airway epithelium; airway surface liquid; bronchial epithelium; cell type; common treatment; cystic fibrosis patients; defined contribution; human model; improved; innovation; intercellular communication; mortality; mouse model; novel; particle; pathogen; promoter; response; single-cell RNA sequencing; targeted treatment; therapeutic development; tissue culture; transcription factor

PROJECT SUMMARY/ABSTRACT Regulation of ion transport across the epithelium is vital to the health and function of the airways. Active and passive ion and water movement is responsible for maintaining a periciliary fluid layer through which cilia can move mucus and protect the airways against particles, irritants, and pathogens. While there is clear evidence of disease caused by specific ion channel mutations (CFTR) as well acquired ion channel dysfunction during/contributing to disease severity (COPD, asthma), the contribution of individual cell types of the pulmonary epithelium to ion transport maintenance is poorly understood. Our experimental evidence demonstrates that alterations in the frequencies of pulmonary ionocytes and neuroendocrine cells in airway epithelial cultures result in dramatic differences in ion transport properties. Altogether, these cell types, along with tuft-like cells, comprise about 0.8% of the total cell numbers in the human tracheal epithelium. Pulmonary ionocytes are a newly identified cell type in the airways with extremely high expression of many ion channels with vital functions in the respiratory tract. The dramatic impact of ionocytes and pulmonary neuroendocrine cells on the ion transport properties of human airway cultures despite their rare frequencies led to our hypothesis that these cell types are highly involved in the regulation and maintenance of ion transport balance across the entire epithelium and are able to impact ion transport functions in other cell types through intercellular communication. By utilizing novel murine models and applying innovative techniques to primary murine and human airway epithelial cells, the research outlined in this proposal will define the contribution of these rare cell types to the overall ion transport functions of the airway epithelium and will also define the role of CFTR in these cells. We will thereby fully characterize the significance of pulmonary ionocytes and neuroendocrine cells to ion transport-mediated airway surface liquid regulation and identify potential cell and ion channel targets for therapeutic treatment of common airway diseases.

项目总结/摘要 调节跨上皮的离子转运对气道的健康和功能至关重要。活性 被动离子和水的运动负责维持纤毛周围的液体层， 可以移动粘液并保护气道免受颗粒物、刺激物和病原体的侵害。虽然有明确的 由特定离子通道突变（CFTR）以及获得性离子通道功能障碍引起的疾病证据 在疾病严重程度（COPD、哮喘）期间/促成疾病严重程度（COPD、哮喘）， 对肺上皮细胞到离子转运维持的了解很少。我们的实验证据 表明在气道中肺离子细胞和神经内分泌细胞频率的改变， 上皮培养物导致离子转运性质的显著差异。总之，这些细胞类型，沿着 簇状细胞占人气管上皮细胞总数的0.8%。肺 离子细胞是一种新发现的气道细胞类型 呼吸道的重要功能。离子细胞和肺神经内分泌的巨大影响 细胞对人气道培养物离子转运特性的影响，尽管它们的频率很罕见， 这些细胞类型高度参与离子转运平衡的调节和维持的假说 并且能够通过以下方式影响其他细胞类型中的离子转运功能： 细胞间通讯通过利用新的小鼠模型和应用创新技术， 小鼠和人类气道上皮细胞，这项研究概述了这项建议将确定的贡献， 这些罕见的细胞类型对气道上皮细胞的整体离子转运功能的影响， 在这些细胞中。因此，我们将充分表征肺离子细胞的意义， 神经内分泌细胞对离子转运介导的气道表面液体的调节，并确定潜在的细胞和 离子通道靶点，用于常见气道疾病的治疗性治疗。