Sensitivity analysis of deterministic signaling pathways models

Puszyński, Krzysztof; Lachor, P.; Kardyńska, Małgorzata; Śmieja, Jarosław

doi:10.2478/v10175-012-0060-3

Cited by 9 publications

(10 citation statements)

References 23 publications

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“…To test the sensitivity of the model to the fitted parameters, we performed sensitivity analysis according to the procedure described in [ 35 ] and in Additional file 8 . The results show that for the time periods of measurement of apoptotic fractions and viability the model outputs are insensitive to the change of parameters values.…”

Section: Introductionmentioning

confidence: 99%

A novel mathematical model of ATM/p53/NF- κB pathways points to the importance of the DDR switch-off mechanisms

et al. 2016

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BackgroundAtaxia telangiectasia mutated (ATM) is a detector of double-strand breaks (DSBs) and a crucial component of the DNA damage response (DDR) along with p53 and NF- κB transcription factors and Wip1 phosphatase. Despite the recent advances in studying the DDR, the mechanisms of cell fate determination after DNA damage induction is still poorly understood.ResultsTo investigate the importance of various DDR elements with particular emphasis on Wip1, we developed a novel mathematical model of ATM/p53/NF- κB pathways. Our results from in silico and in vitro experiments performed on U2-OS cells with Wip1 silenced to 25 % (Wip1-RNAi) revealed a strong dependence of cellular response to DNA damages on this phosphatase. Notably, Wip1-RNAi cells exhibited lower resistance to ionizing radiation (IR) resulting in smaller clonogenicity and higher apoptotic fraction.ConclusionsIn this article, we demonstrated that Wip1 plays a role as a gatekeeper of apoptosis and influences the pro-survival behaviour of cells – the level of Wip1 increases to block the apoptotic decision when DNA repair is successful. Moreover, we were able to verify the dynamics of proteins and transcripts, apoptotic fractions and cells viability obtained from stochastic simulations using in vitro approaches. Taken together, we demonstrated that the model can be successfully used in prediction of cellular behaviour after exposure to IR. Thus, our studies may provide further insights into key elements involved in the underlying mechanisms of the DDR.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0293-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

A novel mathematical model of ATM/p53/NF- κB pathways points to the importance of the DDR switch-off mechanisms

et al. 2016

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“…This work focuses only on examining the impact of model parameters changes on its response. Various techniques have been developed, from local approaches with sensitivity functions [ 11 , 12 ] or sloppy/stiff analysis [ 13 , 14 , 15 ], to global, variance-based methods [ 16 ]. Though some of the papers utilized sensitivity analysis in the context of potential drug targets [ 17 ], the methods employed there did not take into account the relation between drug action and kinetic parameters changes.…”

Section: Introductionmentioning

confidence: 99%

“…In mathematical models describing biochemical reactions, each parameter is related to a single biochemical process, or the sequence of processes simplified to a single-step process, and reflect the kinetic properties of the molecules (e.g., enzymes) involved in this process [ 21 ]. The creation of a parameter ranking facilitates finding a process, the alteration of which, e.g., by drug actions, will lead to significant changes in cellular responses to a given stimuli [ 12 ]. Assuming that parameters are independent from each other and that the drug selectively binds to a single target molecule (and thus, altering the kinetic rate of the process in which the molecule participates), it is the OAT approach that should be used.…”

Section: Introductionmentioning

confidence: 99%

Application of Sensitivity Analysis to Discover Potential Molecular Drug Targets

Kardyńska

Śmieja

Paszek

et al. 2022

IJMS

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Mathematical modeling of signaling pathways and regulatory networks has been supporting experimental research for some time now. Sensitivity analysis, aimed at finding model parameters whose changes yield significantly altered cellular responses, is an important part of modeling work. However, sensitivity methods are often directly transplanted from analysis of technical systems, and thus, they may not serve the purposes of analysis of biological systems. This paper presents a novel sensitivity analysis method that is particularly suited to the task of searching for potential molecular drug targets in signaling pathways. Using two sample models of pathways, p53/Mdm2 regulatory module and IFN-β-induced JAK/STAT signaling pathway, we show that the method leads to biologically relevant conclusions, identifying processes suitable for targeted pharmacological inhibition, represented by the reduction of kinetic parameter values. That, in turn, facilitates subsequent search for active drug components.

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“…The parameters for biological processes are calculated or estimated using the results of biological experiments and thus depend highly on the biological, chemical and physical conditions in cells. Sensitivity analysis of models is usually employed to test their vulnerability to small perturbations of parameters [ 6 ], but when a change of the parameter values is large the model outputs may be significantly different. In systems with switching, the problem of parameter perturbation can cause even greater inaccuracy due to cumulation of two effects: first, the initial state before the switch can be significantly altered, and second, the parameters in the model after a switch are biased.…”

Section: Introductionmentioning

confidence: 99%

Influence of parameter perturbations on the reachability of therapeutic target in systems with switchings

Ochab¹,

Puszyński²,

Świerniak³

2017

BioMed Eng OnLine

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BackgroundExamination of physiological processes and the influences of the drugs on them can be efficiently supported by mathematical modeling. One of the biggest problems is related to the exact fitting of the parameters of a model. Conditions inside the organism change dynamically, so the rates of processes are very difficult to estimate. Perturbations in the model parameters influence the steady state so a desired therapeutic goal may not be reached. Here we investigate the effect of parameter deviation on the steady state in three simple models of the influence of a therapeutic drug on its target protein. Two types of changes in the model parameters are taken into account: small perturbations in the system parameter values, and changes in the switching time of a specific parameter. Additionally, we examine the systems response in case of a drug concentration decreasing with time.ResultsThe models which we analyze are simplified, because we want to avoid influences of complex dynamics on the results. A system with a negative feedback loop is the most robust and the most rapid, so it requires the largest drug dose but the effects are observed very quickly. On the other hand a system with positive feedback is very sensitive to changes, so small drug doses are sufficient to reach a therapeutic target. In systems without feedback or with positive feedback, perturbations in the model parameters have a bigger influence on the reachability of the therapeutic target than in systems with negative feedback. Drug degradation or inactivation in biological systems enforces multiple drug applications to maintain the level of a drug’s target under the desired threshold. The frequency of drug application should be fitted to the system dynamics, because the response velocity is tightly related to the therapeutic effectiveness and the time for achieving the goal.ConclusionsSystems with different types of regulation vary in their dynamics and characteristic features. Depending on the feedback loop, different types of therapy may be the most appropriate, and deviations in the model parameters have different influences on the reachability of the therapeutic target.

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Sensitivity analysis of deterministic signaling pathways models

Cited by 9 publications

References 23 publications

A novel mathematical model of ATM/p53/NF- κB pathways points to the importance of the DDR switch-off mechanisms

A novel mathematical model of ATM/p53/NF- κB pathways points to the importance of the DDR switch-off mechanisms

Application of Sensitivity Analysis to Discover Potential Molecular Drug Targets

Influence of parameter perturbations on the reachability of therapeutic target in systems with switchings

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