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Processes 2014, 2(4), 773-794; doi:10.3390/pr2040773

Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process

Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
These authors contributed equally to this work.
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Received: 29 August 2014 / Revised: 26 September 2014 / Accepted: 8 October 2014 / Published: 17 October 2014
(This article belongs to the Special Issue Modeling and Analysis of Signal Transduction Networks)
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Abstract

Activation and deactivation of hepatic stellate cells (HSCs) is an important mechanism contributing to both healthy liver function and development of liver diseases, which relies on the interplay between numerous signaling pathways. There is accumulating evidence for the regulatory role of microRNAs that are downstream from these pathways in HSC activation. However, the relative contribution of these pathways and interacting microRNA regulators to the activation process is unknown. We pursued a computational modeling approach to explore the timing and regulatory balances that are critical to HSC activation and quiescence. We developed an integrated model incorporating three signaling pathways with crosstalk (NF-κB, STAT3 and TGF-β) and two microRNAs (miR-146a, miR-21) that are differentially regulated by these pathways. Simulations demonstrated that TGF-β-mediated regulation of microRNAs is critical to drive the HSC phenotypic switch from quiescence (miR-146ahigh miR-21low) to an activated state (miR-146alow miR-21high). We found that the relative timing between peak NF-κB and STAT3 activation plays a key role driving the initial dynamics of miR-146a. We observed re-quiescence from the activated HSC state upon termination of cytokine stimuli. Our integrated model of signaling and microRNA regulation provides a new computational platform for investigating the mechanisms driving HSC molecular state phenotypes in normal and pathological liver physiology. View Full-Text
Keywords: hepatic stellate cell; microRNA regulation; NF-κB; STAT3; TGF-β; network model; simulation hepatic stellate cell; microRNA regulation; NF-κB; STAT3; TGF-β; network model; simulation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Kuttippurathu, L.; Parrish, A.; Vadigepalli, R. Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process. Processes 2014, 2, 773-794.

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