Although chronic obstructive pulmonary disease (COPD) occurs predominantly in smokers, it is unknown why only a minority of smokers (~20-40%) develop chronic airflow limitation and/or destruction of distal airspaces (emphysema). Our preliminary work using metabolomics, genomics and animal models has identified dysregulation of sphingolipids as a crucial step in the pathogenesis of COPD and emphysema. The identification of spingolipids such as ceramides can serve as a paradigm for metabolome studies of COPD. This proposal will focus on identifying candidates using the NHLBI sponsored COPDGene cohort, which is a 10,000 subject, highly-phenotyped cohort of smokers with and without COPD. Using this integrated metabolomics-genomics-animal model approach, we anticipate that we will identify other dysregulated pathways that can explain why some smokers get COPD and emphysema yet other smokers do not. The first step (Aim 1) of the project will be to identify novel metabolic pathways in plasma and bronchoalveolar lavage fluid that are dysregulated in COPD and emphysema. Candidate pathways will then be investigated in mice using integrated metabolomic and genomic approaches (Aim 2 and 3). Pathway analysis will be used to identify candidate genes for enzymes that play a role in the dysregulated metabolome (Aim 3). These enzymes will be targeted for further study using animal models (Aim 2) as well as through genomic approaches (Aim 3).

Public Health Relevance

COPD is the 3rd leading cause of death in the United States. This project is likely to result in the identification of dysregulated metabolic pathways that lead smokers to develop COPD phenotypes such as emphysema and frequent exacerbations. Identification of these pathways will allow us to develop novel diagnostic and prognostic assays as well as suggest novel therapeutic targets. (End of Abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory Grants (P20)
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Special Emphasis Panel (ZHL1-CSR-Q (F2))
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Gan, Weiniu
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National Jewish Health
United States
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Cruickshank-Quinn, Charmion I; Jacobson, Sean; Hughes, Grant et al. (2018) Metabolomics and transcriptomics pathway approach reveals outcome-specific perturbations in COPD. Sci Rep 8:17132
Walmsley, Scott; Cruickshank-Quinn, Charmion; Quinn, Kevin et al. (2018) A prototypic small molecule database for bronchoalveolar lavage-based metabolomics. Sci Data 5:180060
Miller, Mikaela A; Danhorn, Thomas; Cruickshank-Quinn, Charmion I et al. (2017) Gene and metabolite time-course response to cigarette smoking in mouse lung and plasma. PLoS One 12:e0178281
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Cruickshank-Quinn, Charmion; Powell, Roger; Jacobson, Sean et al. (2017) Metabolomic similarities between bronchoalveolar lavage fluid and plasma in humans and mice. Sci Rep 7:5108
Halper-Stromberg, Eitan; Cho, Michael H; Wilson, Carla et al. (2017) Visual Assessment of Chest Computed Tomographic Images Is Independently Useful for Genetic Association Analysis in Studies of Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc 14:33-40
Siska, Charlotte; Bowler, Russell; Kechris, Katerina (2016) The discordant method: a novel approach for differential correlation. Bioinformatics 32:690-6
Bowler, Russell P; Jacobson, Sean; Cruickshank, Charmion et al. (2015) Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes. Am J Respir Crit Care Med 191:275-84
Cruickshank-Quinn, Charmion; Quinn, Kevin D; Powell, Roger et al. (2014) Multi-step preparation technique to recover multiple metabolite compound classes for in-depth and informative metabolomic analysis. J Vis Exp :
Carolan, Brendan J; Hughes, Grant; Morrow, Jarrett et al. (2014) The association of plasma biomarkers with computed tomography-assessed emphysema phenotypes. Respir Res 15:127

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