A quarter of patients with chronic obstructive pulmonary disease (COPD) in the United States have no history of smoking. The occupational contribution to development of COPD is significant. Endotoxin is a ubiquitous and poorly recognized environmental and occupational exposure that may cause non-tobacco related COPD. In recent studies, chronic inhalational endotoxin has been associated with the development of obstructive lung disease in both humans and murine models. Despite the importance of endotoxin related lung disease, it has not been well studied. The primary objective of this study is to investigate the biology underlying the development of chronic obstructive lung disease due to long term endotoxin exposure. We hypothesize that specific genes and genes grouped by function or interaction play a role in the development of endotoxin related lung disease. To test this hypothesis, we will select candidate single nucleotide polymorphisms (SNPs) and associated genes by integrating high density customized genotyping data in an exposure-naove "newly hired" cohort of cotton textile workers with gene expression data in a phenotypically validated murine model of chronic endotoxin exposure. Wewill also use contextual information such as functional annotation and protein-protein interactions to re-rank SNPs that fail to reach genome wide significance. Candidate regions will then be tested in a chronically exposed "long term" cohort of cotton textile workers. Validated regions will then be annotated for putative biological function, and an interaction analysis will b performed on all validated regions to infer disease causing mechanisms underlying chronic inhaled endotoxin and obstructive lung disease. As part of the research training program, the principle investigator will complete a Master of Public Health with a concentration in Quantitative Methods in order to acquire the necessary epidemiology and biostatistics skills, as well as relevant bioinformatics tools. This research project will be performed under the mentorship of an established investigator in genetic epidemiology who has studied endotoxin-related lung disease for the past 3 decades.

Public Health Relevance

A quarter of all people in the United States diagnosed with chronic obstructive pulmonary disease (COPD) have never smoked. Other exposures besides tobacco contribute to the development of COPD. The purpose of this study is to examine how endotoxin, a bacterial toxin, can lead to COPD. Our work may lead to new treatments for non-tobacco related COPD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32ES020082-01A1
Application #
8252322
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Humble, Michael C
Project Start
2012-04-15
Project End
2013-05-31
Budget Start
2012-04-15
Budget End
2013-04-14
Support Year
1
Fiscal Year
2012
Total Cost
$66,530
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Lai, Peggy S; Hang, Jing Qing; Zhang, Feng Ying et al. (2014) Gender differences in the effect of occupational endotoxin exposure on impaired lung function and death: the Shanghai Textile Worker Study. Occup Environ Med 71:118-25
Lai, Peggy S; Christiani, David C (2013) Long-term respiratory health effects in textile workers. Curr Opin Pulm Med 19:152-7
Lai, Peggy S; Thompson, B Taylor (2013) Why activated protein C was not successful in severe sepsis and septic shock: are we still tilting at windmills? Curr Infect Dis Rep 15:407-12
Mayaud, Louis; Lai, Peggy S; Clifford, Gari D et al. (2013) Dynamic data during hypotensive episode improves mortality predictions among patients with sepsis and hypotension. Crit Care Med 41:954-62
Lai, P S; Matteau, A; Iddriss, A et al. (2013) An updated meta-analysis to understand the variable efficacy of drotrecogin alfa (activated) in severe sepsis and septic shock. Minerva Anestesiol 79:33-43
Lai, Peggy S; Hofmann, Oliver; Baron, Rebecca M et al. (2013) Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin. PLoS One 8:e62910