Immunometabolic phenotypes in adult severe asthma and disease progression

成人严重哮喘和疾病进展的免疫代谢表型

• 批准号: 10622745
• 负责人: MARK A ARONICA
• 金额: $ 23.6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10622745
• 关键词: Address; Adult; Affect; Asthma; Biological; Bronchodilator Agents; Clinical; Clinical Management; Defect; Disease; Disease Progression; Equation; Future; Glucocorticoids; Immunophenotyping; Inflammation; Investigation; Longitudinal Studies; Lung; Metabolic dysfunction; Molecular; Monitor; National Heart, Lung, and Blood Institute; Outcome; Patients; Phenotype; Predictive Value; Race; Reporting; Research; Research Design; Resolution; Risk; Severity of illness; Social Conditions; Testing; airway hyperresponsiveness; airway inflammation; asthmatic patient; base; cohort; endophenotype; experimental study; follow-up; improved; insight; molecular phenotype; multi-racial; novel therapeutics; parent grant; programs; pulmonary function; recruit; risk stratification; systemic inflammatory response; targeted treatment; therapeutic development; translational approach

PARENT GRANT ABSTRACT The proposed experiments will test the hypothesis: Extensive longitudinal and immunometabolic phenotyping will advance our understanding of the heterogeneous mechanisms for SA and inform future therapeutic development and clinical management strategies. Specifically, comprehensive phenotyping will reveal distinct biological mechanisms and clinical outcomes for SA patients with persistent type 2 inflammation, non-type 2 disease, and defective resolution. Severe asthma (SA) is characterized by persistent airway inflammation, airway hyper-responsiveness, and decreased lung function despite glucocorticoids. Here, we are proposing to extend the NHLBI Severe Asthma Research Program (SARP) for a translational, longitudinal mechanistic study of SA. This longitudinal study design represents an essential “next step” to provide information on the stability of SA endophenotypes and their relationship to disease severity and progression. Investigation into SA airway inflammation has uncovered heterogeneous pathobiology. Approximately 50% of patients are characterized by increased type 2 (T2) inflammation; discoveries that led recently to new T2 targeted therapies. There remains a continuing and critical need to further elucidate mechanisms underlying the distinct pathobiology in subpopulations of SA to provide molecular phenotyping for risk stratification, new therapeutic development, especially for non-T2 inflammation, and precision clinical management. Over the last 6 years, SARP has recruited a large US cohort of SA patients. Subjects were comprehensively characterized at baseline and then monitored over three years of longitudinal follow up, leading to significant new insights into clinical, structural, functional and immunometabolic disturbances in SA. In work in progress, analyses of 3-year longitudinal follow- up has established 3 principal immunophenotypes: (1) persistent T2 inflammation, (2) intermittent T2 inflammation, and (3) persistent non-T2 inflammation. The immunophenotypes had both similarities and differences at presentation with differences evolving further over 3 years of longitudinal follow up (e.g., changes in bronchodilator responsiveness, risk for exacerbations; vide infra). In addition to lung specific inflammation, many SA patients have systemic inflammation, metabolic dysfunction and defects in resolution mechanisms. To address our main hypothesis, we propose a national, multicenter collaborative study with a mechanistic translational approach with 4 specific aims to rigorously and comprehensively investigate the molecular and cellular origin of SA immunometabolic phenotypes and their relationship to disease progression.

专利授权摘要 拟议的实验将检验假设：广泛的纵向和免疫代谢表型 将促进我们对SA异质性机制的理解，并为未来的治疗提供信息。 发展和临床管理策略。具体来说，综合表型分析将揭示不同的 持续性2型炎症的SA患者的生物学机制和临床结局， 疾病，和有缺陷的决议。严重哮喘（SA）的特征在于持续的气道炎症、气道炎症和气道炎症。 高反应性和尽管使用糖皮质激素但肺功能下降。在此，我们建议延长 NHLBI严重哮喘研究计划（SARP），用于SA的平移、纵向机制研究。 这种纵向研究设计代表了提供SA稳定性信息的重要“下一步” 内表型及其与疾病严重程度和进展的关系。SA气道的研究 炎症揭示了异质性病理学。大约50%的患者具有以下特征： 增加2型（T2）炎症;最近导致新的T2靶向治疗的发现。仍然 持续和迫切需要进一步阐明不同病理生物学的机制， SA亚群，为风险分层、新治疗开发提供分子表型， 特别是对于非T2炎症和精确的临床管理。在过去的六年里，SARP已经 招募了大量美国SA患者队列。受试者在基线时进行全面表征，然后 监测超过三年的纵向随访，导致对临床，结构， SA的功能和免疫代谢紊乱。在正在进行的工作中，分析了3年的纵向跟踪- up已经建立了3种主要的免疫表型：（1）持续性T2炎症，（2）间歇性T2 炎症和（3）持续性非T2炎症。免疫表型既有相似性， 在3年的纵向随访中，呈现的差异进一步发展（例如，变化 在支气管扩张剂反应性中，恶化的风险;见下文）。除了肺部特异性炎症外， 许多SA患者存在全身性炎症、代谢功能障碍和消退机制缺陷。到 为了解决我们的主要假设，我们提出了一项全国性的多中心合作研究， 翻译的方法，4个具体的目标，严格和全面地研究分子和 SA免疫代谢表型的细胞起源及其与疾病进展的关系。