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: 10503780
• 负责人: John V Fahy
• 金额: $ 57.5万
• 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/10503780
• 关键词: 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; Epithelial Cells; Exercise; Exercise Test; Exercise Tolerance; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Goals; Image; In Vitro; Inflammation; Inhalation; Inspiratory Capacity; Insulin; Insulin Resistance; Interleukin-6; Interleukins; Knowledge; Lead; 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; base; 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％的成年美国人肥胖，肥胖症在严重哮喘患者中很常见。这 肥胖与严重哮喘之间关联的机制知之甚少，但线索 来自肥胖的代谢后果，包括胰岛素抵抗和全身白细胞介素6 炎。我们最近表明，一部分肥胖哮喘患者具有代谢功能障碍（MD）和 那个肥胖的MD患者比没有MD的肥胖患者患有更严重的哮喘。此外，我们发现 肥胖症中较低的肺功能与MD的度量更密切相比 指数。此外，我们发现肥胖的MD患者对吸入和全身的反应不佳 皮质类固醇。所有这些发现使我们假设肥胖相关的MD和胰岛素耐药性引起 气道病理导致皮质类固醇激素功能障碍。在这里，我们建议对此进行测试 通过全面表征肥胖哮喘患者气道生理和病理学的假设 MD和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 表征有和没有代谢的肥胖哮喘患者的射线照相和生理异常 功能障碍（MD）。在这里，我们将分析计算机断层扫描肺扫描并进行心肺运动 在患有和没有MD的哮喘患者中进行测试。我们假设MD患者具有射线照相 支气管壁厚度和空气捕获的度量，运动过程中遭受动态性过度充电 锻炼不宽容。 AIM 2将表征哮喘患者气道炎症和气道重塑 具有代谢功能障碍；在这里，我们将使用转录组绘制MD哮喘患者的细胞谱 来自诱导的痰液样品的轮廓，并测量了内向支架的基底膜区域厚度 活检样本以检验我们的假设，即MD肥胖患者的气道炎症为2型，并且 这些患者的气道重塑为以上皮下纤维化为特征。 AIM 3将发展基因 与胰岛素相关气道疾病的签名，并确定哮喘患者是否上调这些特征 具有胰岛素抵抗。在这里，我们将利用体外细胞培养和空间转录组学识别基因 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。然后我们会 确定在气道上皮刷子或哮喘的痰细胞中这些基因特征是否上调 IR患者。这些目标共同有助于解决有关疾病知识的重要差距 严重哮喘的肥胖患者运作的机制，并有望提供数据以告知新型 这些患者的治疗方法。