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Bioinformatics Advance Access published online on August 19, 2008
Bioinformatics, doi:10.1093/bioinformatics/btn400
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© The Author (2008). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Model-based analysis of Interferon-β induced signaling pathway

Jaroslaw Smieja 1,*, Mohammad Jamaluddin 2, Allan R. Brasier 2 and Marek Kimmel 3

1 Institute of Automatic Control, Silesian University of Technology, Akademicka 16, 44-101 Gliwice, Poland
2 Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-1060, USA
3Department of Statistics, Rice University, 6100 Main Street, MS-138, Houston, TX 77005, USA

*To whom correspondence should be addressed. Dr. Jaroslaw Smieja, E-mail: Jaroslaw.Smieja{at}polsl.pl


  Abstract

Motivation: Interferon–β induced JAK-STAT signaling pathways contribute to mucosal immune recognition and an anti-viral state. Though the main molecular mechanisms constituting these pathways are known, neither the detailed structure of the regulatory network, nor its dynamics has yet been investigated. The objective of this work is to build a mathematical model for the pathway that would serve two purposes: 1) to reproduce experimental results in simulation of both early and late response to Interferon-β stimulation and 2) to explain experimental phenomena generating new hypotheses about regulatory mechanisms that cannot yet be tested experimentally.

Results: Experimentally determined time dependent changes in the major components of this pathway were used to build a mathematical model describing pathway dynamics in the form of ordinary differential equations. The experimental results suggested existence of unknown negative control mechanisms that were tested numerically using the model. Together, experimental and numerical data show that the epithelial JAK-STAT pathway might be subject to previously unknown dynamic negative control mechanisms: (i) activation of dormant phosphatases and (ii) inhibition of nuclear import of IRF1.

Availability: The model, written in Matlab, is available online at www.stat.rice.edu/~jsmieja/IFN

Contact: Jaroslaw.Smieja{at}polsl.pl

Supplementary information: Supplementary data will be available at Bioinformatics online

Associate Editor: Dr. Trey Ideker

Received on January 9, 2008; revised on June 15, 2008; accepted on July 28, 2008

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