The Early Growth-Response Factor-1 (EGR-1) is a sequence-specific transcription factor that plays a regulatory role in the expression of many genes important in inflammation, cell growth, apoptosis, and the pathogenesis of disease. Several lines of evidence suggest that EGR-1 is involved in the pathogenesis of asthma. First, EGR-1 is located in the """"""""cytokine-gene cluster"""""""" (q31-33) of chromosome 5, a genomic region linked to atopy, airway hyperresponsiveness, and asthma. Second, EGR-1 is expressed in several airway cell types and induced by many cytokines and injurious stimuli found in the airways of asthmatics. Third, EGR-1 is thought to control the expression of several genes involved in the regulation of IgE production, airway inflammation, and smooth muscle contractility. Fourth, egr-1-deficient mice have altered cytokine expression, IgE regulation, and hyporesponsive airways. Finally, we have identified several candidate polymorphisms in the EGR-1 gene that are likely to alter its function. We speculate that these polymorphisms are a significant part of the genetic variability responsible for phenotypic differences among asthmatics. The proposed research will explore the role of EGR-1 in the pathogenesis of asthma and the effect of its genetic variability on asthma phenotype. To accomplish these goals we will pursue 4 Specific Aims: 1) Establish the target genes and molecular mechanisms by which EGR-l modulates atopy and airway responsiveness. 2) Comprehensively screen EGR-1 for additional sequence variants. 3) Evaluate the effect of these sequence variants on gene expression or protein function. 4) Use a family-based association approach to define specific genotypes associated with the development of asthma or a modification of the asthma phenotype. This information should result in a greater understanding of the molecular basis of asthma and may ultimately lead to new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070573-04
Application #
6760069
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Banks-Schlegel, Susan P
Project Start
2001-09-30
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
4
Fiscal Year
2004
Total Cost
$324,000
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
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