Abstract
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 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.
Highlights
The Ras/Raf/MEK/extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade is involved in a panoplyof physiological and pathophysiological processes in the body and is crucial for life
ERK1/2 have shown to be essential but at the same time detrimental to the heart: ERK1/2 mediate cell survival but can mediate cardiomyocyte hypertrophy associated with maladaptive remodeling of the heart and impaired cardiac function
We consider a gene regulatory network for cardiomyocytes given in [14] where we discuss how to use the presented framework in principle to calculate different strategies to act on this network with external stimuli and to find out optimal pharmacological targets
Summary
The Ras/Raf/MEK/ERK1/2 cascade is involved in a panoplyof physiological and pathophysiological processes in the body and is crucial for life. The Ras/Raf/Mek ERK1/2 cascade has ERK as last amplifier. The Ras/Raf/MEK/ERK1/2 cascade integrates extracellular signals from surface receptors to multiple cellular processes such as gene expression or cell survival. Upstream receptors include receptor tyrosine kinases and G protein coupled receptors. The activation of Raf is induced by the small GTPase Ras; Raf in turn phosphorylates and activates MEK, which phosphorylate the effector kinases ERK1/2 at the so-called TEY motif leading to the activation of ERK1/2. The nuclear/cytosolic distribution of ERK1/2 is controlled by scaffold proteins such as KSR, PEA-15 and Sef and by active and passive nuclear translocation processes involving the nuclear pore [1,2,3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
