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: 10529293
• 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/10529293
• 关键词: ATAC-seq; Adrenal Cortex Hormones; Adult; Allergens; Asthma; Bioinformatics; Biological; Cells; 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; Genetic Transcription; Glucocorticoid Receptor; Goals; Health; Healthcare; Histology; Human; Hypertrophy; Image; Immune; Immune Cell Suppression; Infiltration; Inflammation; Inflammatory; Inhalation; Interferon Type II; Knockout Mice; Lung; Lymphocyte; Lymphocytic Infiltrate; MYH11 gene; Mediating; Molecular; Morbidity - disease rate; Mus; Muscle function; Nuclear Translocation; Pathway interactions; Phosphorylation; Post-Translational Regulation; Production; Proliferating; 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; care burden; cytokine; human model; immune cell infiltrate; improved; inhibitor; mouse model; muscular structure; novel; novel therapeutic intervention; p65; receptor; resistance gene; respiratory examination; respiratory smooth muscle; synergism; 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.

项目摘要 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。 发展和健康。吸入性皮质类固醇是控制哮喘症状和疾病的关键 进展然而，患有严重哮喘的儿童对皮质类固醇治疗不敏感或耐药， 需要大剂量全身使用。气道平滑肌（ASM）是调节气道炎症的关键结构细胞， 气道功能和张力。在重度儿童哮喘中，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。然而， 皮质类固醇不敏感或抵抗，特别是在ASM中，仍然不确定。研究报道 Th 1炎症（如Th 1淋巴细胞气道浸润增加所示）与IFNγ之间的相关性 严重的哮喘。此外，我们最近发现，IFNγ和TNFα的联合暴露， 在ASM中诱导皮质类固醇抵抗。这些数据使我们推测IFNγ和TNFα的相互作用 使促炎信号通路，特别是NFκB和JAK/Stat 1，在存在 皮质类固醇通过2个特定目标，我们将使用新的皮质类固醇耐药小鼠和人类模型， 检查ASM的气道炎症、高反应性（AHR）和重塑。具体目标1将测试 IFNγ在激素抵抗期间增强ASM气道高反应性和重塑的假设 过敏性气道炎症虽然具体目标2将检验IFNγ和IFN-γ联合暴露的假设， TNFα打开染色质结构，导致人类小儿ASM的皮质类固醇耐药。这项建议会 包括使用细胞，分子和生物信息学方法来了解IFNγ之间的相互作用， 和TNFα增强ASM的Ca ~（2+）调节机制和转录调节。此外，我们将 检查靶向JAK/Stat通路是否可以改善ASM中皮质类固醇的敏感性， 气道功能这些新的研究将扩大目前对气道结构细胞， 如ASM，出现皮质类固醇耐药，同时也开始确定介导皮质类固醇的机制 严重儿童哮喘的抵抗力。