Mathematical Modelling of the Canonical NF- kappaB Pathway in Bloomington, MN

The regulation of the transcription factor NF-kappa 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-kappa 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-kappa B pathway was developed to study the dynamical properties using a bifurcation analysis. The total NF-kappa B concentration as well as the transcription rate constant of the NF-kappa B inhibitor Ikappa Balphawere identified as two key parameters that influence the dynamics of NF-kappa B. Further, the activation and deactivation of NF-kappa B is tightly regulated by negative feed-back loops. The transcription of the two NF-kappa B inhibitors Ikappa Balphaand A20 is induced by NF-kappa B itself. In this work, a mathematical model was developed comprising both negative feedbacks to determine if post-transcriptional regulation of the two inhibitor m RNAs by the RNA-binding protein RC3H1 can impact the NF-kappa B signal transduction. Additionally, the interplay of the two feedbacks was analysed and cell type specific differences were examined. Again, the total NF-kappa B concentration was found to have a crucial impact. It determines the influence of RC3H1 on the NF-kappa B activity and the interplay of the two feedbacks.