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-1) 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.
As the third leading cause of death in the United States with very few therapies that modify long-term outcomes, chronic obstructive pulmonary disease (COPD) is an important public health concern. The goal of this work is to identify and characterize first the subgroup of COPD patients who are biologically similar to asthma, and then subgroups with more COPD-specific biology. This may lead to the identification of effective therapies for COPD subgroups, particularly for the subgroup more likely to respond to asthma therapeutics.
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