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 哮喘仍然是儿童的重要医疗保健，并对他们的长期影响 发展与健康。吸入皮质类固醇是管理哮喘症状和疾病的关键 进展。但是，严重哮喘的儿童是不敏感或抗性皮质类固醇疗法，领先 气道平滑肌（ASM）是调节的关键结构单元 气道功能和音调。在严重的小儿哮喘中，气道注射，反应强度（AHR）和 重塑继续侵袭性皮质类固醇治疗。然而 皮质类固醇不敏感或抗性，尤其是在ASM中，仍然不确定。研究报告 Th1注射之间的关联，如Th1淋巴细胞气道浸润和IFNγ的相关性 水平和严重的哮喘。此外，我们最近表明，对IFNγ和TNFα的综合暴露独特 在ASM中诱导皮质类固醇。这些数据使我们假设IFNγ和TNFα相互作用 启用促炎信号通路，尤其是NFκB和JAK/STAT1，在存在下保持激活 通过2个特定目的，我们将使用新型的小鼠和人类耐药性的耐药性和人类模型 检查气道注入，反应强度（AHR）和ASM中的重塑。具体目标1将测试 IFNγ在抗体抗性期间增强了IFNγ提高ASM中AIR道高反应性和重塑的假设 过敏性气道注射。而特定的目标2将检验以下假设，即联合暴露于IFNγ和 TNFα打开染色质结构，从而导致人小儿ASM的皮质类固醇。该提议将 涉及使用细胞，分子和生物信息学方法来了解IFNγ之间的相互作用 TNFα增强了ASM中的Ca2+调节机制和转录调节。此外，我们会的 检查靶向JAK/STAT途径是否可以提高ASM中的皮质类固醇激素并改善 气道功能。这些新的研究将扩大人们对气道结构细胞的了解 作为ASM，发展皮质类固醇的耐药性，同时也开始定义培养基皮质类固醇的机制 严重的小儿哮喘的抗性。