Asthma is a disorder arising from chronic inflammation of the airways. The inflamed airways become hyper-responsive to various inhaled stimuli and become obstructed as result of contraction of bronchial smooth muscles. Depletion of the endogenous bronchodilator, s-nitrosoglutathione (GSNO) from the airways of asthmatics and experimental animals suggested that one of the underlying causes of airflow obstruction to be the loss of GSNO from the airway lining fluid. This has been supported by studies in mice deficient in GSNO metabolizing enzyme, s-nitrosoglutathione reductase (GSNOR). Mice deficient in GSNOR were protected from airway hyper-responsivity even in presence of strong inflammation. The long term objective of the current study is to design inhibitors of human GSNOR and evaluate the usefulness of preventing GSNO breakdown in the treatment of asthma. We will use high throughput screening methods to identify compounds that bind human GSNOR. We will further evaluate the potential of the identified compounds as leads for investigating the effects of GSNOR inhibition on airway hyper-responsivity using enzyme kinetics, x-ray crystallography and measurement of changes in the protein s-nitrosylation levels in a cell culture model. The proposed work will lead to identification of compounds that will allow evaluating a new approach for preventing asthmatic episodes in asthma patients. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL087816-01
Application #
7235495
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2007-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$227,250
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Sanghani, Paresh C; Davis, Wilhelmina I; Fears, Sharry L et al. (2009) Kinetic and cellular characterization of novel inhibitors of S-nitrosoglutathione reductase. J Biol Chem 284:24354-62