MOLECULAR BIOLOGY AND GENETICS OF EGR-1 IN ASTHMA

Harvard University (Sch Of Public Hlth), Boston MA

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Abstract

DESCRIPTION (Applicant's Abstract): 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.