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

基本信息

  • 批准号:
    10503780
  • 负责人:
  • 金额:
    $ 57.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目总结/文摘:

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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John V Fahy其他文献

Development of an asthma health-care burden score as a measure of severity and predictor of remission in SARP III and U-BIOPRED: results from two major longitudinal asthma cohorts
开发哮喘保健负担评分作为 SARP III 和 U-BIOPRED 中严重程度的衡量指标和缓解预测因子:来自两个主要纵向哮喘队列的结果
  • DOI:
    10.1016/s2213-2600(24)00250-9
  • 发表时间:
    2025-01-01
  • 期刊:
  • 影响因子:
    32.800
  • 作者:
    Joe G Zein;Nazanin Zounemat-Kermani;Ian M Adcock;Bo Hu;Amy Attaway;Mario Castro;Sven-Erik Dahlén;Loren C Denlinger;Serpil C Erzurum;John V Fahy;Benjamin Gaston;Annette T Hastie;Elliot Israel;Nizar N Jarjour;Bruce D Levy;David T Mauger;Wendy Moore;Michael C Peters;Kaharu Sumino;Elizabeth Townsend;Eugene R Bleecker
  • 通讯作者:
    Eugene R Bleecker

John V Fahy的其他文献

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{{ truncateString('John V Fahy', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 57.5万
  • 项目类别:
Sequential, Multiple Assignment, Randomized Trial in Severe Asthma Protocol (SMART-SA)
严重哮喘方案中的序贯、多重分配、随机试验 (SMART-SA)
  • 批准号:
    10454345
  • 财政年份:
    2017
  • 资助金额:
    $ 57.5万
  • 项目类别:
Sequential, Multiple Assignment, Randomized Trial in Severe Asthma Protocol (SMART-SA)
严重哮喘方案中的序贯、多重分配、随机试验 (SMART-SA)
  • 批准号:
    10221035
  • 财政年份:
    2017
  • 资助金额:
    $ 57.5万
  • 项目类别:
Sequential, Multiple Assignment, Randomized Trial in Severe Asthma Protocol (SMART-SA)
严重哮喘方案中的序贯、多重分配、随机试验 (SMART-SA)
  • 批准号:
    9751962
  • 财政年份:
    2017
  • 资助金额:
    $ 57.5万
  • 项目类别:
Carbohydrate-based Therapy for Lung Disease
以碳水化合物为基础的肺部疾病治疗
  • 批准号:
    9766888
  • 财政年份:
    2016
  • 资助金额:
    $ 57.5万
  • 项目类别:
A thiol-saccharide therapy to treat COVID-19
治疗 COVID-19 的硫醇糖疗法
  • 批准号:
    10226074
  • 财政年份:
    2016
  • 资助金额:
    $ 57.5万
  • 项目类别:
Carbohydrate-based Therapy for Lung Disease
以碳水化合物为基础的肺部疾病治疗
  • 批准号:
    10225939
  • 财政年份:
    2016
  • 资助金额:
    $ 57.5万
  • 项目类别:
Carbohydrate-based Therapy for Lung Disease
以碳水化合物为基础的肺部疾病治疗
  • 批准号:
    9147792
  • 财政年份:
    2016
  • 资助金额:
    $ 57.5万
  • 项目类别:
Epithelial cell reprogramming and mucus gel pathology in self-sustaining type 2 airway niches in asthma
哮喘自我维持型 2 型气道微环境中的上皮细胞重编程和粘液凝胶病理学
  • 批准号:
    10226878
  • 财政年份:
    2012
  • 资助金额:
    $ 57.5万
  • 项目类别:
Exploring the biology of persistent type 2 airway niches in asthma
探索哮喘持续性 2 型气道生态位的生物学
  • 批准号:
    10472526
  • 财政年份:
    2012
  • 资助金额:
    $ 57.5万
  • 项目类别:
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