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)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory Grants (P20)
Project #
5P20HL113445-02
Application #
8454477
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (F2))
Program Officer
Gan, Weiniu
Project Start
2012-04-15
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$1,153,399
Indirect Cost
$285,381
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
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