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).
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)
|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|
|Hughes, Grant; Cruickshank-Quinn, Charmion; Reisdorph, Richard et al. (2014) MSPrep--summarization, normalization and diagnostics for processing of mass spectrometry-based metabolomic data. Bioinformatics 30:133-4|
|Cruickshank-Quinn, Charmion I; Mahaffey, Spencer; Justice, Matthew J et al. (2014) Transient and persistent metabolomic changes in plasma following chronic cigarette smoke exposure in a mouse model. PLoS One 9:e101855|
|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 :|
|Yang, Yanhui; Cruickshank, Charmion; Armstrong, Michael et al. (2013) New sample preparation approach for mass spectrometry-based profiling of plasma results in improved coverage of metabolome. J Chromatogr A 1300:217-26|
|Reisdorph, N; Wechsler, M E (2013) Utilizing metabolomics to distinguish asthma phenotypes: strategies and clinical implications. Allergy 68:959-62|