Analyzing pharmacological intervention points: A method to calculate external stimuli to switch between steady states in regulatory networks

Tim Breitenbach; Chunguang Liang; Niklas Beyersdorf; Thomas Dandekar

doi:10.1371/journal.pcbi.1007075

Analyzing pharmacological intervention points: A method to calculate external stimuli to switch between steady states in regulatory networks

PLoS Comput Biol. 2019 Jul 16;15(7):e1007075. doi: 10.1371/journal.pcbi.1007075. eCollection 2019 Jul.

Authors

Tim Breitenbach¹, Chunguang Liang¹, Niklas Beyersdorf², Thomas Dandekar¹

Affiliations

¹ Lehrstuhl für Bioinformatik, Biozentrum, Universität Würzburg, Würzburg, Germany.
² Institut für Virologie und Immunbiologie, Universität Würzburg, Würzburg, Germany.

Abstract

Once biological systems are modeled by regulatory networks, the next step is to include external stimuli, which model the experimental possibilities to affect the activity level of certain network's nodes, in a mathematical framework. Then, this framework can be interpreted as a mathematical optimal control framework such that optimization algorithms can be used to determine external stimuli which cause a desired switch from an initial state of the network to another final state. These external stimuli are the intervention points for the corresponding biological experiment to obtain the desired outcome of the considered experiment. In this work, the model of regulatory networks is extended to controlled regulatory networks. For this purpose, external stimuli are considered which can affect the activity of the network's nodes by activation or inhibition. A method is presented how to calculate a selection of external stimuli which causes a switch between two different steady states of a regulatory network. A software solution based on Jimena and Mathworks Matlab is provided. Furthermore, numerical examples are presented to demonstrate application and scope of the software on networks of 4 nodes, 11 nodes and 36 nodes. Moreover, we analyze the aggregation of platelets and the behavior of a basic T-helper cell protein-protein interaction network and its maturation towards Th0, Th1, Th2, Th17 and Treg cells in accordance with experimental data.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Computer Simulation*
Models, Biological*
Protein Interaction Maps
T-Lymphocytes, Helper-Inducer / metabolism

Grants and funding

We acknowledge funding by DFG: --Project number 374031971; TR240/INF; platelet results in particular section 4; awarded to TD; --Project number 210879364; grant TR124/B2 awarded to TD and subproject C6 awarded to NB; pertains in particular to all results given in Section 5). --This Publication was supported by the open access fund of the University of Würzburg. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.