Evaluating the Impact of Metabolic Dysfunction on Asthma Pathology and Physiology

评估代谢功能障碍对哮喘病理学和生理学的影响

• 批准号: 10688260
• 负责人: John V Fahy
• 金额: $ 77.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688260
• 关键词: Acceleration; Address; Adrenal Cortex Hormones; Adult; Air; Airway Disease; American; Area; Asthma; Basement membrane; Biopsy; Biopsy Specimen; Body mass index; Body measure procedure; Cardiopulmonary; Cell Culture Techniques; Cells; Data; Disease; Epithelial Cells; Epithelium; Exercise; Exercise Test; Exercise Tolerance; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Goals; Image; In Vitro; Inflammation; Inflammatory; Inhalation; Inspiratory Capacity; Insulin; Insulin Resistance; Interleukin-6; Interleukins; Knowledge; Lung; Lung CAT Scan; Maps; Measures; Mediating; Metabolic; Metabolic dysfunction; Methods; Obesity; Participant; Pathology; Pathway interactions; Patients; Physiological; Physiology; Pulmonary function tests; Research; Resistance; Sampling; Sputum; Subgroup; Testing; Thick; Time; Tissue Banks; Work; X-Ray Computed Tomography; airway epithelium; airway inflammation; airway obstruction; airway remodeling; asthmatic patient; cohort; cytokine; eosinophil; exercise intolerance; genetic signature; lung imaging; neutrophil; novel; obese patients; obesity-associated asthma; programs; pulmonary function; radiological imaging; transcriptome sequencing; transcriptomics

Project Summary/Abstract: More than 40% of adult Americans are obese and obesity is common among patients with severe asthma. The mechanisms underlying the association between obesity and severe asthma are poorly understood, but a clue comes from the metabolic consequences of obesity, which include insulin resistance and systemic interleukin-6 inflammation. We recently showed that a subset of obese asthma patients have metabolic dysfunction (MD) and that obese patients with MD have more severe asthma than obese patients without MD. In addition, we found that lower lung function in obesity is more strongly related to measures of MD than measures of body mass index. Furthermore, we found that obese patients with MD respond poorly to inhaled and systemic corticosteroids. All of these findings lead us to hypothesize that obesity-related MD and insulin resistance causes airway pathology that leads to corticosteroid resistant airway dysfunction. Here, we propose to test this hypothesis by comprehensively characterizing airway physiology and pathology in obese asthma patients with MD and exploring mechanisms by which insulin mediates airway dysfunction. We have 3 aims: Aim 1 will characterize the radiographic and physiologic abnormalities in obese asthma patients with and without metabolic dysfunction (MD). Here we will analyze computed tomography lung scans and perform cardiopulmonary exercise testing in asthma patients with and without MD. We hypothesize that patients with MD have radiographic measures of bronchial wall thickness and air trapping and suffer dynamic hyperinflation during exercise leading to exercise intolerance. Aim 2 will characterize airway inflammation and airway remodeling in asthma patients with metabolic dysfunction; Here, we will map the cellular profile of asthma patients with MD using transcriptomic profiles from induced sputum samples and measure basement membrane zone thickness from endobronchial biopsy samples to test our hypothesis that airway inflammation in obese patients with MD is type-2 low and that these patients have airway remodeling characterized by subepithelial fibrosis. Aim 3 will develop gene signatures of insulin-related airway disease and determine if these signatures are upregulated in asthma patients with insulin resistance. Here we will utilize in vitro cell cultures and spatial transcriptomics to identify gene expression signatures of insulin-mediated airway disease in airway fibroblasts and epithelial cells. We will then determine if these gene signatures are upregulated in airway epithelial brushings or sputum cells from asthma patients with IR. Together these aims will help address an important gap in knowledge about disease mechanisms operating in obese patients with severe asthma and promises to provide data to inform novel treatment approaches for these patients.

项目摘要/摘要： 超过 40% 的美国成年人肥胖，并且肥胖在严重哮喘患者中很常见。这 肥胖与严重哮喘之间的关联机制尚不清楚，但有一个线索 来自肥胖的代谢后果，包括胰岛素抵抗和全身性白细胞介素 6 炎。我们最近发现，一部分肥胖哮喘患者存在代谢功能障碍 (MD)，并且 患有 MD 的肥胖患者比没有 MD 的肥胖患者患有更严重的哮喘。此外，我们还发现 与体重测量相比，肥胖患者肺功能较低与 MD 测量的相关性更强 指数。此外，我们发现患有 MD 的肥胖患者对吸入性和全身性药物反应不佳 皮质类固醇。所有这些发现使我们推测肥胖相关的 MD 和胰岛素抵抗会导致 导致皮质类固醇抵抗性气道功能障碍的气道病理学。在这里，我们建议测试一下 通过全面描述肥胖哮喘患者的气道生理学和病理学特征得出的假设 MD 并探索胰岛素介导气道功能障碍的机制。我们有 3 个目标： 目标 1 将 描述患有或不患有代谢性哮喘的肥胖哮喘患者的放射学和生理学异常特征 功能障碍（MD）。在这里，我们将分析计算机断层扫描肺部扫描并进行心肺锻炼 对患有或不患有 MD 的哮喘患者进行测试。我们假设 MD 患者有影像学检查 测量支气管壁厚度和空气滞留，并在运动过程中遭受动态过度充气 锻炼不宽容。目标 2 将描述哮喘患者气道炎症和气道重塑的特征 代谢功能障碍；在这里，我们将利用转录组学绘制患有 MD 的哮喘患者的细胞图谱 诱导痰样本的轮廓并测量支气管内膜基底膜区的厚度 活检样本来检验我们的假设，即肥胖 MD 患者的气道炎症为 2 型低水平，并且 这些患者存在以上皮下纤维化为特征的气道重塑。目标3将开发基因 胰岛素相关气道疾病的特征，并确定这些特征在哮喘患者中是否上调 与胰岛素抵抗。在这里，我们将利用体外细胞培养和空间转录组学来鉴定基因 气道成纤维细胞和上皮细胞中胰岛素介导的气道疾病的表达特征。我们随后将 确定这些基因特征是否在气道上皮刷检或哮喘痰细胞中上调 IR 患者。这些目标共同将有助于解决疾病知识方面的重要差距 机制在患有严重哮喘的肥胖患者中发挥作用，并有望提供数据来指导新的研究 针对这些患者的治疗方法。