Chronic Obstructive Pulmonary Disease (COPD) affects over 18 million Americans. It is clear that the major environmental risk factor for this debilitating syndrome is cigarette smoking. It is not clear, however, what factors are responsible for the fact that some smokers develop the disease while most do not. Studies of potential therapies have been hampered by the lack of easily measurable characteristics that predict the course of the disease. Most studies have used measures of lung function as a marker of disease activity. Such studies typically require large numbers of patients and an observation period of months to years. This application proposes studies to develop alternative biomarkers associated with COPD. The research proposed will develop a set of candidate biomarkers by utilizing expression array profiling to characterize gene expression patterns in lung tissue and peripheral blood associated with the presence of COPD. These candidates will then be assessed in studies performed in populations previously characterized for COPD-related phenotypes: the Boston Early Onset COPD Study and the Normative Aging Study. The initial studies will involve expressionprofiling in both lung tissue and peripheral blood in samples obtained from patients undergoing pulmonary resections at Brigham and Women's Hospital. Samples from 20 patients with airflow obstruction on spirometry and emphysema demonstrated on chest CT scans will be compared to samples from 20 matched control patients. State of the art bioinformatic analytic techniques will be used to analyze these data and develop a list of candidate biomarkers based on expression differences. Polymorphisms in the candidate genes will then be studied for genetic association in two characterized populations with different disease distributions. The Boston Early Onset COPD Study consists of patients who have been diagnosed at an early age with severe COPD and their family members. In contrast, the Normative Aging Study includes participants with a broad spectrum of COPD. Studies in these populations will be directed at establishing whether differences in gene expression or gene polymorphisms are associated with COPD. It is hoped that these markers will provide insight into disease pathogenesis and serve as outcome assessment parameters.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072303-04
Application #
6945172
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Croxton, Thomas
Project Start
2002-09-23
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$573,557
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Hersh, Craig P; Silverman, Edwin K; Gascon, Jody et al. (2011) SOX5 is a candidate gene for chronic obstructive pulmonary disease susceptibility and is necessary for lung development. Am J Respir Crit Care Med 183:1482-9
Bhattacharya, Soumyaroop; Srisuma, Sorachai; Demeo, Dawn L et al. (2009) Molecular biomarkers for quantitative and discrete COPD phenotypes. Am J Respir Cell Mol Biol 40:359-67
DeMeo, Dawn L; Mariani, Thomas; Bhattacharya, Soumyaroop et al. (2009) Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. Am J Hum Genet 85:493-502
Bhattacharya, Soumyaroop; Srisuma, Sorachai; Demeo, Dawn L et al. (2006) Microarray data-based prioritization of chronic obstructive pulmonary disease susceptibility genes. Proc Am Thorac Soc 3:472
Bhattacharya, Soumyaroop; Mariani, Thomas J (2005) Transformation of expression intensities across generations of Affymetrix microarrays using sequence matching and regression modeling. Nucleic Acids Res 33:e157