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.

抽象的慢性下呼吸道疾病是美国和全世界发病和死亡的主要原因。目前尚无有效的疾病缓解疗法，并且尚不清楚如何定义和最佳地治疗哮喘和 COPD（慢性阻塞性肺病；慢性支气管炎和肺气肿）。这项机制研究旨在定义适合的新途径基于患病气道上皮细胞作为慢性疾病上游驱动因素的作用的治疗干预气道疾病。作为该提案的基础，多项人类临床和转化研究以及过敏原、烟雾和病毒诱导的动物模型已经证实了致病性上皮细胞的相关性。 COPD 和哮喘中衍生的细胞因子 IL-33。然而，仍然存在的一个主要知识差距是理解核隔离 IL-33 被激活并从患病气道细胞分泌的机制来驱除炎症。在这里，我们提供初步数据，证明人类慢性阻塞性肺病 (COPD) 气道上皮细胞细胞表达水平升高的截短、剪接的 IL-33 同种型，该同种型能够逃逸细胞核隔离被充分分泌。我们的分析进一步揭示了这种分泌型 IL-33 的新特征同种型，包括翻译后修饰、与外泌体相关伴侣的相互作用，以及利用外泌体运输途径进行分泌。因此，本研究旨在阐明影响这些新发现的 IL-33 生物学特征对慢性气道疾病发病机制的影响。目标1将定义 IL-33 与外泌体伴侣的相互作用如何增强细胞因子分泌和受体激活使用人类细胞和小鼠气道疾病模型并结合验证来驱动气道疾病人类呼吸道疾病标本。目标 2 将研究翻译后修饰在通过类似的方法增强 IL-33 分泌和受体激活以传播疾病使用人类细胞和小鼠模型并在人类样本中进行验证。这些目标共同将解决引发和维持慢性气道疾病的病理序列中的关键步骤，阐明在粘膜界面靶向外泌体介导的细胞因子分泌的新方法。