Fungal Asthma and Lung Innate Immunity

真菌性哮喘和肺部先天免疫

基本信息

批准号：
10386885
负责人：
Yin Chen
金额：
$ 51.76万
依托单位：
UNIVERSITY OF ARIZONA
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：
2020-05-07 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10386885
关键词：
Abbreviations Acute Air Alternaria Animal Model Antifungal Agents Aspergillus Asthma Bronchoalveolar Lavage Cells Chronic Cladosporium Clinical Coin Data Analyses Data Set Detection Development Epithelial Epithelial Cells Exposure to Foundations Fungal Spores Fungi Model Genes Genetic Polymorphism Homeostasis Hospitalization Human Immune response Immunology Impairment Individual Infection Inflammasome Inflammation Integrins Interferons Knockout Mice Knowledge Link Lung Lymphoid Cell Mediating Metaplastic Cell Modeling Molds Molecular Molecular and Cellular Biology Mucous body substance Mus National Heart, Lung, and Blood Institute Natural Immunity Pathogenesis Pathway interactions Pattern Pattern recognition receptor Persons Pharmaceutical Preparations Phenotype Prevalence Production RARRES3 gene RNA Reporting Reproduction spores Research Risk Factors Role Sampling Seasons Signal Transduction Subcategory TLR3 gene Testing United States National Institutes of Health airway epithelium airway hyperresponsiveness asthma exacerbation asthma model asthmatic atopy fungus genetic signature immunogenic meter mouse model neutrophil novel prevent programs public health relevance pulmonary function receptor resilience respiratory response sensor side effect single-cell RNA sequencing statistics therapeutic development transcriptomics type I interferon receptor

项目摘要

Abstract: Environmental mold (fungal) exposure has long been recognized as a critical risk factor for asthma and asthma exacerbation. The prevalence of fungal sensitization can be up to 48% in asthmatics and fungal asthma is oftentimes poorly managed with frequent exacerbations and hospitalizations. Efforts to reduce indoor fungal exposure by cleaning have been proven impossible in the recent HEAL study. However, an average person exposing to a large number of fungal spores each day, up to 50,000 spores per cubic meter of air during the fungal season, has no detectable respiratory abnormality and not all individuals with fungal sensitization develop asthma. Thus, it is significant to understand the mechanistic basis of this resilience to maintain airway homeostasis despite the impact of abundant asthmagenic substances produced by fungi. Interestingly, IFN signatures were discovered in the fungal asthma model using live Alternaria spores. Epithelial cells were found to sense fungal spores by triggering IFN-I/III production as well as their downstream signaling cascades. IFN-I receptor blockade or deficiency augmented asthmatic phenotypes, suggesting a protective role of IFN-I against asthma. Thus, our overall hypothesis is that fungal spore sensing activates protective IFN-I/III pathway and the impairment of this protection leads to asthma. To test this hypothesis, we will elucidate the protective function of IFN-I/III in the fungal asthma model using a set of knockout mice. Then, we will determine the mechanistic basis of fungal detection and innate defense. Finally yet importantly, we will examine IFN signatures in clinical samples from human asthma with or without fungal sensitization by utilizing datasets and samples from a NIH- supported Asthma Research Program. The completion of this proposal will advance our knowledge about the pathogenesis of fungal asthma, and establish a foundation for the further therapeutic development to treat this type of asthma.

抽象的：环境霉菌（真菌）暴露长期以来被认为是哮喘和哮喘的关键危险因素恶化。哮喘患者中真菌致敏的患病率可高达 48%，而真菌性哮喘是通常管理不善，经常恶化和住院。努力减少室内真菌最近的 HEAL 研究已证明通过清洁进行暴露是不可能的。然而，一个普通人每天接触大量的真菌孢子，期间每立方米空气多达50,000个孢子真菌季节，没有可检测到的呼吸道异常，并且并非所有个体都有真菌过敏发展为哮喘。因此，了解这种维持气道弹性的机制基础具有重要意义。尽管受到真菌产生的大量致哮喘物质的影响，但仍保持体内平衡。有趣的是，干扰素使用活链格孢属孢子在真菌哮喘模型中发现了特征。发现上皮细胞通过触发 IFN-I/III 的产生及其下游信号级联来感知真菌孢子。干扰素I 受体阻断或缺陷会增强哮喘表型，表明 IFN-I 具有保护作用哮喘。因此，我们的总体假设是真菌孢子传感激活保护性 IFN-I/III 途径，并且这种保护作用的损害会导致哮喘。为了检验这个假设，我们将阐明保护功能使用一组基因敲除小鼠在真菌哮喘模型中使用 IFN-I/III。然后，我们将确定机械真菌检测和先天防御的基础。最后但重要的是，我们将检查临床中的干扰素特征通过利用 NIH 的数据集和样本，从有或没有真菌致敏的人类哮喘中获取样本支持哮喘研究计划。该提案的完成将提高我们对真菌性哮喘的发病机制，并为进一步治疗该疾病的开发奠定基础哮喘类型。