Resolution:
## Figure 3.
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 |