There are approximately 45 million current smokers and 46 million former smokers who are at increased risk for tobacco-related disease in the United States. The public health implications of this widespread environmental exposure are profound;tobacco smoke is the leading preventable cause of death in the United States and is projected to cause nearly 450 million deaths worldwide during the next 50 years. Despite the causal role of cigarette smoking in lung cancer and COPD, only 10-20% of smokers develop these diseases. There are few indicators of which smokers are at highest risk for disease, and it is unclear why individuals remain at high risk decades after they have stopped smoking. Current standard methods for quantifying exposure to tobacco smoke are limited in their ability to accurately assess cumulative dose and past exposure, and they do not capture the physiologic host response to tobacco exposure. We have previously shown that cigarette smoke causes an airway-wide epithelial cell """"""""field of injury"""""""" and that gene expression, in airway epithelial cells obtained at bronchoscopy, reflects host response to smoking. We propose here to extend the """"""""field of injury"""""""" concept to easily-accessible airway epithelial cells that can be obtained from nasal or buccal mucosa in a non-invasive fashion. By measuring global gene expression at these sites using a new """"""""all-exon"""""""" expression platform, we will develop a series of biomarkers that assess host response to current tobacco exposure (active vs. passive vs. never smokers), intensity of current exposure, cumulative exposure among current smokers, time since last exposure among smokers who recently quit, and lifetime exposure. Furthermore, we will develop molecular pathway-based gene expression biomarkers that may be more accurate markers of individual responses to tobacco smoking. We also propose to correlate airway gene expression biomarkers with lung function and systemic markers of oxidative stress and inflammation, setting the stage for a more detailed understanding of how variability in epithelial response contributes to variability in disease-related pulmonary and systemic sequelae of tobacco smoke exposure. These studies will establish a new non-invasive tool that can be used to measure the host responses to tobacco smoke that can be used in subsequent large scale population studies as part of the Genes and Environment Initiative.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01ES016035-03
Application #
7629122
Study Section
Special Emphasis Panel (ZES1-LKB-E (BR))
Program Officer
Shaughnessy, Daniel
Project Start
2007-08-15
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
3
Fiscal Year
2009
Total Cost
$573,459
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Zeskind, Julie E; Lenburg, Marc E; Spira, Avrum (2008) Translating the COPD transcriptome: insights into pathogenesis and tools for clinical management. Proc Am Thorac Soc 5:834-41

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