Identifying the Th2 endotype in COPD: clinical and pathologic implications

识别 COPD 中的 Th2 内型：临床和病理意义

• 批准号: 9238788
• 负责人: Stephanie A Christenson
• 金额: $ 17.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238788
• 关键词: Adrenal Cortex Hormones; Affect; Air; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Automobile Driving; Biological; Biological Markers; Biology; Biometry; Biopsy; Blood; Bone Density; Breathing; Bronchoscopy; Cause of Death; Characteristics; Chronic Obstructive Airway Disease; Clinical; Clinical Investigator; Clinical Research; Data; Development; Discipline; Disease; Education; Eosinophilia; Epithelial; Epithelial Cells; Fibrosis; Fracture; Funding; Future; Gene Expression; Gene Expression Profile; Genomics; Goals; Grant; Health; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 beta; Interleukin-13; Interleukin-17; Interleukin-5; Lead; Measurement; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; National Heart, Lung, and Blood Institute; Outcome; Pathogenesis; Pathologic; Patients; Phenotype; Population; Public Health; Randomized Controlled Trials; Research; Research Methodology; Respiratory physiology; Risk; Sampling; Serum; Site; Smoker; Sputum; Statistical Computing; Study Subject; Subgroup; Symptoms; TNF gene; Testing; Therapeutic; Therapeutic Trials; Thick; Training; Training Programs; United States; Validation; Work; airway hyperresponsiveness; airway inflammation; airway obstruction; atopy; base; clinical predictors; clinically relevant; cohort; cost; cytokine; disease heterogeneity; effective therapy; eosinophil; genetic signature; genomic tools; hands on research; insight; longitudinal course; mast cell; multidisciplinary; novel; patient subsets; periostin; predicting response; predictive marker; prevent; programs; public health relevance; response; skills; therapeutic development; tool; transcriptome sequencing; translational research program; translational scientist; treatment strategy

 DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is estimated to affect 10% of the world's population. Despite the significant impact of the disease there are few therapies that modify outcomes. There is a subset of patients with COPD who display clinical features more consistent with asthma (e.g. hyperresponsiveness, atopy). More progress has been made into understanding the fundamental mechanisms of disease and identifying effective therapies in asthma than in COPD. Identifying those subjects in which asthma-associated immune responses contribute significantly to disease may broaden our understanding of COPD and lead to the identification of a COPD subgroup ("endotype") particularly responsive to asthma therapeutics. Our lab has identified a gene signature of Th2-associated inflammation that is induced in a pathologically and clinically distinct subgroup of asthma ("Th2 high" endotype), and predicts response to existing therapeutics. In preliminary data I show that airway epithelial Th2 high gene signatures are associated with decrements in lung function in two COPD cohorts and with increased airway biopsy eosinophil counts at baseline and improvement in air trapping with ICS in a randomized controlled trial in COPD. I hypothesize that Th2 high gene signatures will identify a clinically and pathologically distinct subset of patients with COPD in which the Th2 immune response is essential to disease pathogenesis ("Th2 high COPD endotype"). I propose to study these Th2 high gene signatures in the well-phenotyped longitudinal SPIROMICS COPD cohort, with the objective of characterizing the Th2 high COPD endotype based on clinical and pathological parameters (Aim 1), and identifying non-invasive biomarkers that may be used to study this group in future studies (Aim 2). I will then use the generated analysis workflow to study whether gene signatures of COPD-specific inflammatory mediators (IL-17, TNFa, IL-1ß) also identify clinically distinct endotypes. In preliminary data I show that there is evidence for other COPD endotypes; an IL-17 associated bronchial epithelial gene signature is associated with declining lung function in COPD, and identifies a subgroup distinct from the one identified by Th2 high gene signatures. This proposal will lead to essential insights into the mechanisms driving disease in subsets of COPD patients. It will also lay the essential groundwork for future clinical studies of endotype-specific outcomes in COPD and mechanism-based therapeutic trials which may lead to the identification of effective therapies for COPD. A multi-disciplinary mentoring committee whose expertise spans the relevant disciplines of airway biology (Drs.Woodruff, Erle, Fahy, and Sheppard), genomics (Drs. Woodruff, Sen, and Erle), and clinical research methods and biostatistics (Drs. Woodruff, Sen, Fahy, and Calfee) will guide the progress of the proposed research. I have developed an intensive training plan that includes their mentorship, as well as a directed hands-on research program, and a didactic training program to refine my skills in clinical research methods and genomics. With the support of this K23, the research and education agenda I have devised will assist me in achieving my long-term goal of becoming an independent clinical and translational investigator in COPD research.

 描述(申请人提供)：慢性阻塞性肺疾病(COPD)估计影响10%的世界人口。尽管这种疾病的影响很大，但很少有治疗方法可以改变结果。有一部分COPD患者表现出与哮喘更一致的临床特征(例如，高反应性、特应性)。与慢性阻塞性肺疾病相比，在了解疾病的基本机制和确定有效的治疗方法方面取得了更多的进展。确定与哮喘相关的免疫反应对疾病有显著贡献的受试者可能会扩大我们对COPD的理解，并导致识别出对哮喘治疗特别敏感的COPD亚群(内型)。我们的实验室已经确定了Th2相关性炎症的基因特征，这种炎症在病理和临床上不同的哮喘亚群(“Th2高”内型)中诱导，并预测对现有治疗方法的反应。在一项随机对照试验中，初步数据I显示，在两个COPD队列中，呼吸道上皮细胞Th2高基因信号与肺功能下降、基线时的气道活检嗜酸性粒细胞计数增加以及ICS的空气滞留改善有关。我假设Th2高基因信号将识别临床和病理上不同的COPD患者亚群，其中Th2免疫反应在疾病发病机制中至关重要(“Th2高COPD内型”)。我建议在表型良好的纵向SPIROMICS COPD队列中研究这些Th2高基因信号，目的是基于临床和病理参数来表征Th2高COPD内型(目标1)，并识别可在未来研究中用于研究这一群体的非侵入性生物标志物(目标2)。然后，我将使用生成的分析工作流程来研究COPD特异性炎症介质(IL-17、TNFa、IL-1？)的基因签名是否也能识别临床上不同的内型。在初步数据中，我表明还有其他COPD内型的证据；IL-17相关的支气管上皮基因特征与COPD患者的肺功能下降有关，并确定了一个不同于Th2高基因特征的亚群。这一建议将导致对COPD患者亚群疾病驱动机制的重要洞察。这也将为未来COPD内型特异性结果的临床研究和可能导致确定COPD有效治疗方法的基于机制的治疗试验奠定必要的基础。一个多学科指导委员会，其专业知识涵盖呼吸道生物学(Woodruff、Erle、Fahy和Seppard博士)、基因组学(Woodruff、Sen和Erle博士)以及临床研究方法和生物统计学(Woodruff、Sen、Fahy和Calfee博士)等相关学科，将指导拟议研究的进展。我已经制定了一项强化培训计划，其中包括他们的指导，以及一项指导实践研究计划，以及一项指导性培训计划，以完善我在临床研究方法和基因组学方面的技能。在K23的支持下，我制定的研究和教育议程将帮助我实现成为COPD研究的独立临床和翻译研究员的长期目标。