COPD represents the fourth leading cause of death in the United States, and is predicted to become the third most common cause of death and the fifth most common cause of disability in the world by the year 2020. COPD is often induced by direct or passive exposure to cigarette smoke. Prolonged cigarette smoke exposure can lead to inflammatory cell recruitment followed by airspace destruction and emphysema. Deficiency in the activity of a-1-antitrypsin (SERPINA1) is a major factor of genetic susceptibility for the development of emphysema. Overwhelming evidence suggests the presence of additional genetic factors contributing to the development of COPD in the general population. Using a combination of genetic linkage, microarray gene expression profiling and genetic association studies we have identified serine protease inhibitor (Serpin) E2 as a novel candidate susceptibility gene for COPD. SERPINE2 is a major tissue and cell-associated inhibitor of thrombin and plasmin, but not elastase, and has been shown to promote extracellular matrix production and inhibit apoptosis. The role of this protein in the pulmonary system has not been previously explored. We have shown that: 1) The gene for SERPINE2 lies within a previously defined linkage region for early-onset COPD on chromosome 2, with maximal evidence for peak linkage when assuming a gene-by-smoking environment interaction; 2) SERPINE2 expression is regulated during lung development, with maximal expression coincident with establishment of alveolar structure; 3) SERPINE2 expression is significantly correlated with measures of poor physiological function in human COPD patients; 4) Genetic association with COPD is observed for multiple SERPINE2 polymorphisms and haplotypes in a family-based population and has been replicated in a case-control population; 5) SERPINE2 is expressed in conducting airway epithelium, within small and intermediate airways, and in basal cells of stratified airways. We hypothesize that SERPINE2 deficiency leads to susceptibility to cigarette smoke-induced lung damage and emphysema. In an effort to begin to identify the role of this protein in lung maturation, homeostasis and susceptibility to COPD we will; 1) examine the physiological role of SERPINE2 in normal lung homeostasis and 2) test SERPINE2 for a physiological role in maintenance of lung structure following cigarette smoke exposure in mice. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21ES014372-03
Application #
7879052
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Nadadur, Srikanth
Project Start
2006-12-01
Project End
2010-11-30
Budget Start
2008-06-01
Budget End
2010-11-30
Support Year
3
Fiscal Year
2008
Total Cost
$118,013
Indirect Cost
Name
University of Rochester
Department
Pediatrics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Solleti, Siva Kumar; Srisuma, Sorachai; Bhattacharya, Soumyaroop et al. (2016) Serpine2 deficiency results in lung lymphocyte accumulation and bronchus-associated lymphoid tissue formation. FASEB J 30:2615-26
Bhattacharya, Soumyaroop; Mariani, Thomas J (2013) Systems biology approaches to identify developmental bases for lung diseases. Pediatr Res 73:514-22
Bhattacharya, Soumyaroop; Mariani, Thomas J (2009) Array of hope: expression profiling identifies disease biomarkers and mechanism. Biochem Soc Trans 37:855-62