Identifying the Th2 endotype in COPD: clinical and pathologic implications

 描述（由申请人提供）：据估计，慢性阻塞性肺疾病（COPD）影响世界人口的10%。尽管该疾病的显著影响，但很少有治疗方法可以改变结果。有一部分COPD患者的临床特征与哮喘更为一致（如高反应性、特应性）。在了解疾病的基本机制和确定哮喘的有效治疗方法方面取得了比COPD更多的进展。鉴定其中哮喘相关免疫应答对疾病有显著贡献的那些受试者可以拓宽我们对COPD的理解，并导致鉴定对哮喘治疗剂特别响应的COPD亚组（“内型”）。我们的实验室已经确定了Th 2相关炎症的基因特征，该基因特征在病理学和临床上不同的哮喘亚组（“Th 2高”内型）中诱导，并预测对现有疗法的反应。在初步数据中，我显示气道上皮Th 2高基因特征与两个COPD队列的肺功能下降相关，与基线时气道活检嗜酸性粒细胞计数增加相关，并在COPD随机对照试验中与ICS改善空气潴留相关。我假设Th 2高基因特征将鉴定具有COPD的患者的临床和病理学上不同的亚组，其中Th 2免疫应答对于疾病发病机理是必需的（“Th 2高COPD内型”）。我建议在表型良好的纵向SPIROMICS COPD队列中研究这些Th 2高基因特征，目的是基于临床和病理学参数表征Th 2高COPD内型（目的1），并确定可用于在未来研究中研究该组的非侵入性生物标志物（目的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，TNF α，IL-1 β）的基因特征是否也可以识别临床上不同的内源性。在初步数据中，我表明有其他COPD内在型的证据; IL-17相关的支气管上皮基因特征与COPD肺功能下降有关，并确定了一个与Th 2高基因特征不同的亚组。这一提议将导致对COPD患者亚群中驱动疾病的机制的重要见解。它还将为未来COPD内型特异性结局的临床研究和基于机制的治疗试验奠定必要的基础，这些研究可能导致确定COPD的有效治疗方法。一个多学科指导委员会将指导拟议研究的进展，该委员会的专业知识涵盖气道生物学（Woodruff、Erle、Fahy和Sheppard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）的相关学科。我已经制定了一个强化培训计划，其中包括他们的指导，以及指导性的动手研究计划，以及教学培训计划，以提高我在临床研究方法和基因组学方面的技能。在K23的支持下，我设计的研究和教育议程将帮助我实现成为COPD研究的独立临床和转化研究者的长期目标。

 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.