New model structure required to characterize NF-κB activation in microglia. (A) NF-κB activity during the first 10 minutes following stimulation was only highly sensitive to seven of the 26 rate parameters. (B) By using an IKK signal derived from experimental measurements as the model input, the outer feedback loop can be removed (indicated by gray lines), isolating the downstream NF-κB activation module with IκBα feedback. Similarly, once the concentration of nuclear NF-κB is known, this signal can be used to drive the upstream IKK activation network independently of the downstream module. (C) Model structure from the original model (top) and the new model (bottom). (D) Simulations with parameters estimated for the existing model (dashed line) and the new model (solid line) using the experimental IKK curve as input. The inset provides a detailed view of the model fits during the initial activation phase. (E) The results of 1980 randomly initialized parameter estimates for each model were checked for statistical consistency with the data using Fisher's Method (see Methods) and binned according to p-value. No estimated parameter sets with the original model achieved a P-value >10-7 (red), while nearly half the estimated parameter sets with the new model (blue) had P > 0.01.
Sheppard et al. BMC Bioinformatics 2011 12:276 doi:10.1186/1471-2105-12-276