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ERK: A Key Player in the Pathophysiology of Cardiac Hypertrophy
Article

How to Steer and Control ERK and the ERK Signaling Cascade Exemplified by Looking at Cardiac Insufficiency

by 1,*,†, 2,3,† and 1,†
1
Biozentrum, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
2
Institute of Pharmacology and Toxicology, Versbacher Straße 9, 97078 Würzburg, Germany
3
Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(9), 2179; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092179
Received: 6 March 2019 / Revised: 16 April 2019 / Accepted: 24 April 2019 / Published: 2 May 2019
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK Thr 188 phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations. View Full-Text
Keywords: optimal pharmacological modulation; efficient intervention points; ERK signaling; optimal treatment strategies; optimal drug targeting; optimal drug combination optimal pharmacological modulation; efficient intervention points; ERK signaling; optimal treatment strategies; optimal drug targeting; optimal drug combination
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MDPI and ACS Style

Breitenbach, T.; Lorenz, K.; Dandekar, T. How to Steer and Control ERK and the ERK Signaling Cascade Exemplified by Looking at Cardiac Insufficiency. Int. J. Mol. Sci. 2019, 20, 2179. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092179

AMA Style

Breitenbach T, Lorenz K, Dandekar T. How to Steer and Control ERK and the ERK Signaling Cascade Exemplified by Looking at Cardiac Insufficiency. International Journal of Molecular Sciences. 2019; 20(9):2179. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092179

Chicago/Turabian Style

Breitenbach, Tim, Kristina Lorenz, and Thomas Dandekar. 2019. "How to Steer and Control ERK and the ERK Signaling Cascade Exemplified by Looking at Cardiac Insufficiency" International Journal of Molecular Sciences 20, no. 9: 2179. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092179

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