Published ahead of print on October 5, 2007, doi:10.1165/rcmb.2007-0151OC Am. J. Respir. Cell Mol. Biol., Volume 38, Number 3, March 2008, 324-336 A more recent version of this article appeared on March 1, 2008
Submitted on April 26, 2007 A Functional and Regulatory Map of AsthmaNoa Novershtern1,1 Faculty of Medicine, The Hebrew University, School of Computer Science and Engineering, Jerusalem, Israel, 2 Department of Molecular Genetics and Biotechnology, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 3 Department of Computer science and Applied Mathematics, The Weizmann Institute of Science, Rehovot, Israel, 4 University of Pittsburgh School of Medicine, Dorothy P and Richard P Simmons Center for Interstitial Lung Diseases, Division of Pulmonary and Critical Care Medicine, Pittsburgh, PA, USA * To whom correspondence should be addressed. E-mail: kaminskin{at}upmc.edu.
The prevalence and morbidity of asthma, a chronic inflammatory airway disease, is increasing. Animal models provide a meaningful but limited view of the mechanisms of asthma in humans. To provide a systems level view of asthma we compiled a gene expression compendium from five publicly available mouse microarray datasets and a gene knowledge base of 4305 gene annotation sets. Using this collection we generated a high level map of the functional themes that characterize animal models of asthma, dominated by innate and adaptive immune response. We used Module Networks analysis to identify co-regulated gene modules. The resulting modules reflect four distinct responses to treatment, including early response, general induction, repression and IL13 dependent response. One module with a persistent induction in response to treatment is mainly composed of genes with suggested roles in asthma, suggesting a similar role for the other module members. Analysis of IL13 dependent response using protein interaction networks highlights a role for TGF
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1 as a key regulator of asthma. Our analysis demonstrates the discovery potential of systems level approaches and provides a framework for applying such approaches to asthma.
