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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

基本信息

批准号：
10298837
负责人：
Preston E Bratcher
金额：
$ 43.87万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
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/10298837
关键词：
Active Ion Transport Affect Airway Disease Airway Resistance Animals Asthma CRISPR/Cas technology Cell Count Cells Chronic Chronic Obstructive Airway 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 Structure of respiratory epithelium 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

项目摘要

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/文摘