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.

项目总结 哮喘仍然是儿童的重大医疗负担，并对他们的 发展和健康。吸入糖皮质激素是控制哮喘症状和疾病的关键 进步。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，导致 高剂量全身用药的必要性。气道平滑肌(ASM)是一种关键的结构细胞，调节 呼吸道功能和声调。在严重的儿童哮喘中，呼吸道炎症、高反应性(AHR)和 尽管接受了积极的皮质类固醇治疗，重塑仍在继续。然而，潜在的生物学机制， 皮质类固醇不敏感或耐药，尤其是在ASM中，仍未明确。研究报告称 Th1型炎症与干扰素γ的相关性研究 以及严重的哮喘。此外，我们最近发现，干扰素γ和肿瘤坏死因子α的联合暴露是独特的 在ASM中诱导皮质类固醇耐药。这些数据使我们假设干扰素γ和肿瘤坏死因子α相互作用 使促炎信号通路，特别是核因子κB和JAK/STAT1，在存在时保持激活 皮质类固醇。通过两个特定的目标，我们将使用新的小鼠和人类皮质类固醇耐药模型 检测ASM的气道炎症、高反应性(AHR)和重塑。特定目标1将测试 干扰素γ增强激素抵抗期间ASM的高反应性和重塑的假说 过敏性呼吸道炎症。而《特定目标2》将检验这样一种假设，即联合接触干扰素γ和 肿瘤坏死因子α开放染色质结构，导致儿科ASM对糖皮质激素耐药。这项提议将 使用细胞、分子和生物信息学方法了解干扰素γ之间的相互作用 和肿瘤坏死因子α增强钙离子调控机制和转录调控。此外，我们还将 研究靶向JAK/STAT通路是否可以改善ASM对皮质类固醇的敏感性和改善 呼吸道功能。这些新颖的研究将扩大目前对呼吸道结构细胞，如 作为ASM，在产生皮质类固醇抵抗的同时，也开始定义调节皮质类固醇的机制 重症儿童哮喘的耐药性。