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：
10056131
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/10056131
关键词：
Abbreviations Acute Air Alternaria Animal Model Antifungal Agents Antiviral Agents Aspergillus Asthma Bronchoalveolar Lavage Cells Chronic Cladosporium Clinical Coin Data Analyses Data Set Detection Development Epithelial Epithelial Cells Epithelium Exposure to Foundations Fungal Spores Fungi Model Genes Genetic Polymorphism Homeostasis Hospitalization Human Immune response Immunology Impairment Individual 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 Respiratory physiology 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 immunogenic meter mouse model neutrophil novel prevent programs public health relevance 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：长期以来，环境模具（真菌）暴露已被认为是哮喘和哮喘的关键危险因素恶化。哮喘和真菌哮喘的真菌敏化的患病率最高可高达48％经常经常发生病情和住院治疗，经常管理不善。减少室内真菌的努力在最近的治疗研究中，通过清洁暴露是不可能的。但是，一个普通人每天暴露于大量的真菌孢子，每立方米的空气最多可容纳50,000个孢子真菌季节，没有可检测的呼吸系统异常，而不是所有具有真菌敏化的人发展哮喘。因此，了解这种弹性的机械基础很重要稳态尽管真菌产生了丰富的哮喘性物质。有趣的是，ifn 使用现场替代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的产生以及其下游信号级联，感知真菌孢子。 ifn-i 受体阻滞或缺乏症增强哮喘表型，表明IFN-1的保护作用哮喘。因此，我们的总体假设是真菌孢子感应激活保护性IFN-I/III途径和这种保护的损害会导致哮喘。为了检验这一假设，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的IFN-I/III。然后，我们将确定机械真菌检测和天生防御的基础。最后，重要的是，我们将检查临床中的IFN签名通过使用NIH-的数据集和样品，来自人类哮喘的样品，具有或不具有真菌敏化的样本支持哮喘研究计划。该提案的完成将提高我们对真菌哮喘的发病机理，并为进一步的治疗发展建立基础类型的哮喘。