Modelling and analysis of the NF-_63KB [NF kappa B] signalling pathway and development of a thermodynamically consistent modelling approach for reaction rules

Viac o knihe

Intracellular signal transduction involves complex biochemical reaction networks that are often difficult to understand intuitively. This thesis explores mathematical modeling of these networks using ordinary differential equations, enabling analysis through systems theoretical methods. The first part focuses on modeling the NF-?B signal transduction pathway and analyzing the biological significance of specific mechanisms. The second part addresses methodological challenges in modeling signal transduction networks and introduces a novel approach that aims to resolve these issues. The TKM approach is expanded to incorporate reaction rules, merging rule-based modeling with thermodynamic consistency and formalized model reduction. A key aspect of this method is the concept of interaction factors, which help parameterize the effects of bindings on reaction equilibrium and velocity. This significantly reduces the number of required model parameters while enhancing parameterization flexibility. The influence of symmetric complexes on parameterization is also considered. An implementation of the approach in Mathematica is briefly described, along with an extension that improves algorithm efficiency through rule-level reduction. The approach is exemplified with a model of phosducin phosphorylation in the eye's light adaptation process.