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: 10684256
• 负责人: MARK A ARONICA
• 金额: $ 323.4万
• 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/10684256
• 关键词: Acceleration; Address; Adult; Asthma; Automobile Driving; Biological; Bronchodilator Agents; CD8-Positive T-Lymphocytes; Cells; Characteristics; Clinical; Clinical Management; Defect; Disease; Disease Progression; Epithelial Cells; Epithelium; Functional disorder; Future; Genetic; Genomics; Glucocorticoids; Heterogeneity; Image; Immune; Immune response; Immunophenotyping; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Investigation; Knowledge; Leukocytes; Ligands; Longitudinal Studies; Lung; Macrophage; Mediator; Metabolic dysfunction; Metadata; Molecular; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Natural Killer Cells; Obesity; Outcome; Pathway interactions; Patients; Phenotype; Physiology; Publishing; Research; Research Design; Resolution; Risk; Severities; Severity of illness; Sputum; Structure-Activity Relationship; System; Systems Analysis; Testing; Time; Trans-Omics for Precision Medicine; airway epithelium; airway hyperresponsiveness; airway inflammation; asthmatic patient; cohort; design; endophenotype; experimental study; follow-up; insight; insulin regulation; lipid mediator; longitudinal design; metabolomics; microbiome; molecular phenotype; novel therapeutics; phenotypic data; programs; pulmonary function; pulmonary function decline; receptor; recruit; repaired; respiratory; response; risk stratification; societal costs; systemic inflammatory response; targeted treatment; therapeutic development; translational approach

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.

抽象的 提出的实验将检验假设：广泛的纵向和免疫代谢 表型将提高我们对SA的异质机制的理解并告知 未来的治疗发展和临床管理策略。具体，全面 表型将揭示SA患者的不同生物学机制和临床结果 持续的2型感染，非型2疾病和缺陷分辨率。 严重的哮喘（SA）的特征是持续的气道注入，气道高反应性和 尽管糖皮质激素，肺功能降低。在这里，我们提议扩展NHLBI严重哮喘 研究计划（SARP），用于SA的翻译，纵向机械研究。这项纵向研究 设计代表了一个必不可少的“下一步”，以提供有关SA内表型稳定性和的信息 它们与疾病的严重程度和进展的关系。 对SA气道炎症的调查已经发现了异质的病理生物学。约有50％ 患者的特征是2型（T2）炎症增加。最近导致新T2的发现 靶向疗法。仍然需要持续且迫切需要进一步阐明基本机制 SA亚群中的独特病原体学为风险分层提供分子表型，新的 治疗性发育，特别是用于非T2感染和精确临床管理。 在过去的六年中，SARP招募了一大批美国SA患者。受试者是全面的 在基线时进行表征，然后在三年的纵向随访中监测，导致显着 SA中对临床，结构，功能和免疫代谢灾害的新见解。正在进行的工作， 3年纵向随访的分析已经建立了3种主要免疫表型：（1）持续的T2 炎症，（2）间歇性T2炎症和（3）持续的非T2炎症。免疫表型 出现时有相似性和差异，差异在3年以内进一步发展 纵向随访（例如，支气管扩张剂的反应性变化，加重风险；视频下属）。 除肺特异性炎症外，许多SA患者患有全身性炎症，代谢功能障碍 和分辨率机制的缺陷。为了解决我们的主要假设，我们提出了一个国家，多中心 通过机械转化方法进行的协作研究，具有4个特定旨在严格和 全面研究SA免疫代谢表型的分子和细胞来源 与疾病进展的关系。