Airway Structural Cells and Corticosteroid Resistance in Asthma

哮喘中的气道结构细胞和皮质类固醇抵抗

• 批准号: 10094507
• 负责人: Rodney Britt
• 金额: $ 45.43万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-20 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10094507
• 关键词: ATAC-seq; Adrenal Cortex Hormones; Adult; Allergens; Asthma; Bioinformatics; Biological; Cells; Cellular Structures; Child; Childhood; Childhood Asthma; Chromatin; Chromatin Structure; Chronic; Clinical; Complex; DNA; Data; Deposition; Development; Disease; Disease Progression; Dose; Exhibits; Exposure to; Extracellular Matrix; Functional disorder; Genes; Glucocorticoid Receptor; Goals; Health; Healthcare; Histology; Human; Hypertrophy; Image; Immune; Immune Cell Suppression; Infiltration; Inflammation; Inflammatory; Inhalation; Interferon Type II; Knockout Mice; Lung; Lymphocyte; MYH11 gene; Mediating; Molecular; Mus; Muscle function; Nuclear Translocation; Pathway interactions; Phosphorylation; Post-Translational Regulation; Production; Regulatory Pathway; Reporting; Resistance; Role; Side; Signal Pathway; Smooth Muscle; Steroid Resistance; Steroid therapy; Steroids; Symptoms; TNF gene; Testing; Therapeutic; Transcriptional Regulation; airway hyperresponsiveness; airway inflammation; airway obstruction; airway remodeling; allergic airway inflammation; asthmatic; cytokine; human model; improved; inhibitor/antagonist; mouse model; muscular structure; novel; novel therapeutic intervention; p65; receptor; resistance gene; respiratory smooth muscle; transcriptome sequencing

PROJECT SUMMARY Asthma remains a significant healthcare burden for children and has a long-term impact on their development and health. Inhaled corticosteroids are key for managing asthmatic symptoms and disease progression. However, children with severe asthma are insensitive or resistant corticosteroid therapies, leading to the need for systemic use at high doses. Airway smooth muscle (ASM) is a key structural cell that regulates airway function and tone. In severe pediatric asthma, airway inflammation, hyperresponsiveness (AHR), and remodeling continues despite aggressive corticosteroid treatments. Yet the underlying biological mechanisms of corticosteroid insensitivity or resistance, particularly in ASM, remain undefined. Studies have reported associations between Th1 inflammation, as indicated by increased Th1 lymphocyte airway infiltration and IFNγ levels, and severe asthma. Additionally, we recently showed that combined exposure to IFNγ and TNFα uniquely induces corticosteroid resistance in ASM. These data have led us to hypothesize that IFNγ and TNFα interactions enable pro-inflammatory signaling pathways, notably NFκB and JAK/Stat1, to remain activated in the presence of corticosteroids. Via 2 Specific Aims, we will use novel mouse and human models of corticosteroid resistance to examine airway inflammation, hyperresponsiveness (AHR), and remodeling in ASM. Specific Aim 1 will test the hypothesis that IFNγ enhances airway hyperresponsiveness and remodeling in ASM during steroid resistant allergic airway inflammation. While Specific Aim 2 will test the hypothesis that combined exposure to IFNγ and TNFα opens chromatin structure, leading to corticosteroid resistance in human pediatric ASM. This proposal will involve using cellular, molecular, and bioinformatic approaches to understand how interactions between IFNγ and TNFα enhance Ca2+ regulatory mechanisms and transcriptional regulation in ASM. Furthermore, we will examine whether targeting the JAK/Stat pathway can improve corticosteroid sensitivity in ASM and improve airway function. These novel studies will expand the current understanding of how airway structural cells, such as ASM, develop corticosteroid resistance while also beginning to define mechanisms that mediate corticosteroid resistance in severe pediatric asthma.

项目概要 哮喘仍然是儿童的一个重大医疗负担，并对他们的健康产生长期影响 吸入皮质类固醇是控制哮喘症状和疾病的关键。 然而，患有严重哮喘进展的儿童对皮质类固醇疗法不敏感或耐药，导致 气道平滑肌（ASM）是调节的关键结构细胞。 气道功能和张力。严重的小儿哮喘、气道炎症、高反应性 (AHR) 和 尽管进行了积极的皮质类固醇治疗，重塑仍在继续，但其潜在的生物学机制仍然存在。 研究报告称，皮质类固醇不敏感或耐药，特别是在 ASM 中，仍不清楚。 Th1 炎症之间的关联，如 Th1 淋巴细胞气道浸润增加和 IFNγ 所示 此外，我们最近发现联合暴露于 IFNγ 和 TNFα 具有独特的作用。 诱导 ASM 中的皮质类固醇抵抗。这些数据使我们认为 IFNγ 和 TNFα 存在相互作用。 使促炎信号通路（特别是 NFκB 和 JAK/Stat1）在存在时保持激活 通过 2 个具体目标，我们将使用新型小鼠和人类皮质类固醇耐药模型。 检查 ASM 中的气道炎症、高反应性 (AHR) 和重塑。 IFNγ 增强 ASM 类固醇抵抗期间气道高反应性和重塑的假设 过敏性气道炎症，而特定目标 2 将检验将 IFNγ 暴露与过敏性气道炎症相结合的假设。 TNFα 打开染色质结构，导致人类儿童 ASM 出现皮质类固醇耐药。 涉及使用细胞、分子和生物信息方法来了解 IFNγ 之间的相互作用 TNFα 增强 ASM 中的 Ca2+ 调节机制和转录调节。 检查靶向 JAK/Stat 通路是否可以提高 ASM 中的皮质类固醇敏感性并改善 这些新颖的研究将扩大目前对气道结构细胞如何发挥作用的理解。 作为 ASM，发展皮质类固醇抵抗，同时也开始定义介导皮质类固醇的机制 严重小儿哮喘的抵抗力。