Genome-wide association studies (GWAS) have identified replicated associations with COPD susceptibility, including the chromosome 15 locus {CHRNA3/5, IREB2), HHIP, and FAM13A. Multiple studies have also examined genome-wide gene expression profiles in patients with COPD. Gene expression profiling can identify novel COPD genes and help define the pathways by which these GWAS-discovered genes affect COPD. Preliminary data from biological and functional validation studies suggests that IREB2, one such gene identified through gene expression profiling and GWAS in human COPD, may influence COPD through effects on autophagy. This approach has pointed to a novel pathway in COPD, namely autophagy. Autophagy has been shown to play a role in common diseases, and our group has demonstrated the potential relevance of autophagy and apoptosis in emphysema. In this project, we will test two hypotheses: (1) Gene expression profiling in human COPD lung tissue and mouse models will identify novel genes for COPD and genes whose expression is correlated with IREB2, HHIP, and FAM13A, in order to elucidate the pathways of these genes'actions in COPD. (2) IREB2, a COPD susceptibility gene identified through gene expression profiling and GWAS, when induced by cigarette smoke regulates the autophagic process, which facilitates downstream apoptosis promoting the development of emphysema. We will address the following Specific Aims: (1) Human Gene Expression Profiling: We will perform micro-array gene expression profiling in human lung tissue samples to identify genes that are differentially expressed between COPD cases and controls. Gene expression will be validated in airway epithelial cells and alveolar macrophages from former smokers with and without COPD to determine tissue specificity of gene expression. (2) Gene Expression in Murine Models: We will perform micro-array gene expression profiling in lung tissue in 2 wild-type strains with differing susceptibility to cigarette smoke-induced emphysema and in 3 knock-out mouse models { Ireb2-/-, Hhip-/- ,Fam13a-/-) before and after cigarette smoke exposure and in a cell model of airway epithelial cells cultured at an air-liquid interface to identify genes involved in COPD development in these animals. (3) Ireb2-/- and autophagy: We will determine the functional role of Ireb2 in susceptibility to experimental cigarette smoke-induced emphysema. At the conclusion of this project, we will have identified novel genes for COPD and improved our understanding of the roles of HHIP, FAM13A, and IREB2 in COPD, with specific attention to the effects on autophagy and apoptosis pathways. The assessment of human and murine gene expression in this project will complement the genetics and epigenetics methods in Projects 1 and 3, respectively. Integration of these datasets will expand our knowledge of the functional genomics of COPD.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability in the U.S. The Genomics of COPD Study will help us understand the biology of COPD and the genetic factors that affect a person's risk of developing COPD in response to cigarette smoking. This information may eventually lead to new tests or new treatments for COPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL105339-01A1
Application #
8210647
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-08-17
Budget End
2012-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$583,166
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Polverino, Francesca; Laucho-Contreras, Maria E; Petersen, Hans et al. (2017) A Pilot Study Linking Endothelial Injury in Lungs and Kidneys in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 195:1464-1476
Qiu, Weiliang; Guo, Feng; Glass, Kimberly et al. (2017) Differential connectivity of gene regulatory networks distinguishes corticosteroid response in asthma. J Allergy Clin Immunol :
Busch, Robert; Hobbs, Brian D; Zhou, Jin et al. (2017) Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects. Am J Respir Cell Mol Biol 57:35-46
Morrow, Jarrett D; Zhou, Xiaobo; Lao, Taotao et al. (2017) Functional interactors of three genome-wide association study genes are differentially expressed in severe chronic obstructive pulmonary disease lung tissue. Sci Rep 7:44232
Yun, Jeong H; Morrow, Jarrett; Owen, Caroline A et al. (2017) Transcriptomic Analysis of Lung Tissue from Cigarette Smoke-Induced Emphysema Murine Models and Human Chronic Obstructive Pulmonary Disease Show Shared and Distinct Pathways. Am J Respir Cell Mol Biol 57:47-58
Sonawane, Abhijeet Rajendra; Platig, John; Fagny, Maud et al. (2017) Understanding Tissue-Specific Gene Regulation. Cell Rep 21:1077-1088
Hayden, Lystra P; Hardin, Megan E; Qiu, Weiliang et al. (2017) Asthma Is a Risk Factor for Respiratory Exacerbations Without Increased Rate of Lung Function Decline: Five-Year Follow-up in Adult Smokers From the COPDGene Study. Chest :
Lopes-Ramos, Camila M; Paulson, Joseph N; Chen, Cho-Yi et al. (2017) Regulatory network changes between cell lines and their tissues of origin. BMC Genomics 18:723
Paulson, Joseph N; Chen, Cho-Yi; Lopes-Ramos, Camila M et al. (2017) Tissue-aware RNA-Seq processing and normalization for heterogeneous and sparse data. BMC Bioinformatics 18:437
Hobbs, Brian D; de Jong, Kim; Lamontagne, Maxime et al. (2017) Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat Genet 49:426-432

Showing the most recent 10 out of 101 publications