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Non-Classical Cytokine Secretion in Chronic Airway Disease

慢性气道疾病中的非经典细胞因子分泌

基本信息

批准号：
10649572
负责人：
Jennifer Alexander-Brett
金额：
$ 52.81万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649572
关键词：
Acute Address Affinity Airway Disease Allergens Alternaria Animal Model Asthma Automobile Driving Binding Biological Assay Biology Bronchoalveolar Lavage Bypass Cause of Death Cell Nucleus Cell model Cell secretion Cells Chronic Chronic Bronchitis Chronic Disease Chronic Obstructive Pulmonary Disease Clinical Research Complex Coupled Cytoplasm Data Development Diagnosis Disease Disease model Endosomes Enzyme-Linked Immunosorbent Assay Epithelial Cells Epithelium Exhibits Exons Foundations Heat-Shock Proteins 70 Human IL8 gene In Vitro Inflammation Interferometry Knowledge Length Liquid substance Lower respiratory tract structure Mass Spectrum Analysis Measures Mediating Mediator Messenger RNA Metaplasia Molecular Molecular Chaperones Morbidity - disease rate Mucous Membrane Mucous body substance Mus Necrosis Nuclear Pathogenesis Pathogenicity Pathologic Pathway interactions Peptide Signal Sequences Phosphorylation Play Post-Translational Protein Processing Process Production Protein Isoforms Protein Secretion Proteins Proteomics Public Health Pulmonary Emphysema RNA Splicing Reagent Receptor Activation Receptor Signaling Research Respiratory Tract Diseases Role Signal Transduction Smoke Source Specimen Sphingomyelinase Structure Structure of parenchyma of lung System Testing Therapeutic Intervention United States Validation Viral Virus Western Blotting Work X-Ray Crystallography airway epithelium airway obstruction asthma exacerbation chronic respiratory disease cytokine disease phenotype effective therapy exosome genome wide association study in vivo insight knock-down live cell imaging mimetics mortality mouse model mutant novel novel strategies progenitor protein expression public health relevance receptor receptor binding recruit trafficking translational study

项目摘要

Abstract Chronic lower respiratory tract disease is a major cause of morbidity and mortality in the U.S. and worldwide. Currently there are no effective disease-modifying therapies and it remains unclear how to define and optimally treat disease endotypes within the spectrum of asthma and COPD (chronic obstructive pulmonary disease; chronic bronchitis and emphysema). This mechanistic research aims to define new pathways amenable to therapeutic intervention based on the role of diseased airway epithelial cells as an upstream driver of chronic airway disease. As a foundation for this proposal, multiple human clinical and translational studies as well as allergen- smoke- and virus-induced animal models have solidified the relevance of the pathogenic epithelial- derived cytokine IL-33 in COPD and asthma. However, a major knowledge gap that remains is understanding the mechanism by which nuclear-sequestered IL-33 can be activated and secreted from diseased airway cells to drive inflammation. Here we present preliminary data that demonstrates human COPD airway epithelial cells express increased levels of a truncated, spliced IL-33 isoform, which is capable of escaping nuclear sequestration to be abundantly secreted. Our analysis further revealed novel features of this secreted IL-33 isoform including post-translational modification, interaction with exosome-associated chaperones, and utilization of exosome trafficking pathways for secretion. Accordingly, this study aims to elucidate the impact of these newly-discovered features of IL-33 biology on the pathogenesis of chronic airway disease. Aim 1 will define how IL-33 interaction with exosomal chaperones enhances cytokine secretion and receptor activation to drive airway disease, using human cellular and mouse airway disease models coupled with validation in human airway disease specimens. Aim 2 will investigate the role of post-translational modification in augmenting IL-33 secretion and receptor activation to propagate disease, through an analogous approach using human cellular and mouse models with validation in human specimens. Together, these aims will address key steps in the pathologic sequence that initiates and sustains chronic airway disease, illuminating novel ways to target exosome-mediated cytokine secretion at the mucosal interface.

摘要