Analysis of an apoptotic core model focused on experimental design using artificial data.
The activation of caspases is a central mechanism in apoptosis. To gain further insights into complex processes like this, mathematical modelling using ordinary differential equations (ODEs) can be a very powerful research tool. Unfortunately, the lack of measurement data is a common problem in building such kinetic models, because it practically constrains the identifiability of the model parameters. An existing mathematical model of caspase activation during apoptosis was used in order to design future experimental setups that will help to maximise the obtained information. For this purpose, artificial measurement data are generated in silico to simulate potential experiments, and the model is fitted to this data. The model is also analysed using observability gramian and sensitivity analyses. The used analysis methods are compared. The artificial data approach allows one to make conclusions about system properties, identifiability of parameters and the potential information content of additional measurements for the used caspase activation model. The latter facilitates to improve the experimental design of further measurements significantly. The performed analyses reveal that several kinetic parameters are not at all, or only scarcely, identifiable, and that measurements of activated caspase 8 will maximally improve the parameter estimates. Furthermore, we can show that many assays with inhibitor of apoptosis protein (IAP) knockout cells only provide redundant information for our needs and as such do not have to be carried out.
Schlatter
R
R
University of Stuttgart, Institute for System Dynamics, Stuttgart, Germany. rebekka.schlatter@isys.uni-stuttgart.de
Conzelmann
H
H
Gilles
E D
ED
Sawodny
O
O
Sauter
T
T
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D003198:Computer Simulation; D008954:Models, Biological
D051017:Apoptosis Regulatory Proteins