Mechanisms of airway Th2 inflammation in asthma

哮喘气道 Th2 炎症的机制

• 批准号: 9109012
• 负责人: John V Fahy
• 金额: $ 72.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109012
• 关键词: Acute; Address; Affect; Alleles; American; Asthma; Basal Cell; Biology; Biopsy; Blood Cells; CD4 Positive T Lymphocytes; Cells; Clinical; Clinical Research; Data; Disease; Emergency department visit; Environment; Epithelial; Epithelial Cells; Epithelium; Gene Expression; Genes; Genetic Polymorphism; Genetic study; Goals; Heterogeneity; Human; Immune response; Immunity; Infection; Inflammation; Instruction; Interleukin-13; Interleukin-5; Irrigation; Knowledge; Lead; Measures; Mediator of activation protein; Methods; Molecular; Patients; Phenotype; Population; Principal Investigator; Protein Isoforms; Public Health; Publications; Research; Role; Signal Transduction; Single Nucleotide Polymorphism in Regulatory Sequence; Societies; Source; Sputum; Stimulus; Subgroup; Testing; Th2 Cells; Therapeutic; United States; Variant; Viral; adaptive immunity; airway epithelium; airway inflammation; asthmatic; cell type; cost; cytokine; disease heterogeneity; eosinophilic inflammation; genetic signature; genetic variant; genome wide association study; improved; molecular phenotype; mouse model; novel; novel strategies; peripheral blood; programs; receptor; response; treatment response

Asthma is a major public health problem in the United States affecting over 23 million Americans and costing US society $56 billion annually. Despite advances in treatment of asthma, there remains significant unmet therapeutic need, and large subgroups of asthmatics have poor asthma control despite current asthma treatment. Consequently, asthma exacerbations, often precipitated by viral airway infections, continue to result in 2 million emergency room visits a year in the US. The largest molecular phenotype of asthma Is one that is driven by TH2 inflammation and characterized by eosinophilic inflammation, and the project proposed here focuses on clinical studies ofthe mechanisms of TH2 inflammation, including how TH2 inflammation can be amplified during viral-Induced asthma exacerbations. A key rationale for the research aims we propose here Is the increasing recognition that signals from the epithelium to innate cells contribute Importantly to mechanisms of airway Inflammation. The signals we propose to focus on are IL-33 and Its receptor (ST2) and the interactions of IL-33 with ST2-bearing innate helper type 2 cells (iH2) cells, a novel lineage-negative population of cells that secrete IL-5 and IL-13 In response to IL-33. iH2 cells represent a novel cellular source of TH2 cytokines and a cell type that this PPG hypothesizes to have a central role In mechanisms of airway TH2 Inflammation in asthma. Coincident with recent discoveries about iH2 cells has been publication of GWAS studies showing that genetic polymorphisms in IL-33 and ST2 are among a relatively short list of genes consistently associated with asthma. All of these new data suggest new ways by which airway epithelial cells can initiate and amplify type 2 Immune responses In the airway, and we will explore these new possibilities in three aims: Aim 1 will determine the role of IH2 cells as cellular mediators of TH2 inflammation. Aim 2 will determine how IL-33 regulates airway TH2 Inflammation during asthma exacerbations. Aim 3 will determine how genetic variants in ST2 Influence airway TH2 inflammation. In tackling these alms we will advance knowledge for mechanisms of airway TH2 Inflammation in asthma. RELEVANCE (See instructions): Asthma is a common disease and a major public health problem. It cannot be cured and many patients are not optimally controlled using current treatments. Our project will help advance understanding of basic mechanisms of airway Inflammation in patients with asthma and help Identify new approaches for treatment.

在美国，哮喘是影响超过2300万美国人的主要公共卫生问题 美国社会每年560亿美元。尽管在治疗哮喘方面，但仍未达到明显的未得到满足 尽管当前哮喘 治疗。因此，通常由病毒气道感染引起的哮喘恶化继续 导致200万急诊室在美国访问。哮喘的最大分子表型是 这是由Th2炎症驱动的，并以嗜酸性炎症为特征，该项目提出了 这里重点介绍TH2炎症机制的临床研究，包括Th2炎症 在病毒诱导的哮喘加重过程中可以扩增。研究目的的关键基本原理 在这里提出的是，人们越来越认识到，从上皮到先天细胞的信号有助于 重要的是气道炎症机制。我们建议关注的信号是IL-33及其 受体（ST2）和IL-33与含有ST2的先天辅助2型细胞（IH2）细胞的相互作用，这是一种新型 分泌IL-5和IL-13的细胞谱系阴性群体响应IL-33。 IH2细胞代表 Th2细胞因子的新细胞来源和该PPG的细胞类型假设在 哮喘中气道Th2炎症的机制。与有关IH2细胞的最新发现一致 GWAS研究的发表表明，IL-33和ST2中的遗传多态性是 相对较短的基因列表与哮喘一致相关。所有这些新数据都提出了新方法 哪些气道上皮细胞可以启动和扩增气道中的2型免疫反应，我们将 在三个目标中探索这些新可能性：AIM 1将确定IH2细胞作为细胞介质的作用 Th2炎症。 AIM 2将确定IL-33如何调节哮喘中气道Th2炎症 恶化。 AIM 3将决定ST2中的遗传变异如何影响气道Th2炎症。在 解决这些施舍，我们将促进有关哮喘中气道Th2炎症机制的知识。 相关性（请参阅说明）： 哮喘是一种常见的疾病，也是一个重大的公共卫生问题。它不能治愈，许多患者是 使用当前治疗方法不是最佳控制的。我们的项目将有助于提高对基本的理解 哮喘患者气道炎症机制，并有助于识别新的治疗方法。