Mathematical Modelling of the Canonical NF- B Pathway

The regulation of the transcription factor NF- B plays a central role in physiological processes by influencing cell differentiation, proliferation and survival. Experiments revealed great differences in the dynamical behaviour of NF- B ranging from sustained oscillations to damped oscillations and monotone increase evolving to a stable steady state. In this work, a theoretical approach was used to determine internal sources of the observed variability in the dynamics. A core model of the canonical NF- B pathway was developed to study the dynamical properties using a bifurcation analysis. The total NF- B concentration as well as the transcription rate constant of the NF- B inhibitor I Ba were identified as two key parameters that influence the dynamics of NF- B.

Further, the activation and deactivation of NF- B is tightly regulated by negative feed-back loops. The transcription of the two NF- B inhibitors I Ba and A20 is induced by NF- B itself. In this work, a mathematical model was developed comprising both negative feedbacks to determine if post-transcriptional regulation of the two inhibitor mRNAs by the RNA-binding protein RC3H1 can impact the NF- B signal transduction. Additionally, the interplay of the two feedbacks was analysed and cell type specific differences were examined. Again, the total NF- B concentration was found to have a crucial impact. It determines the influence of RC3H1 on the NF- B activity and the interplay of the two feedbacks.