ANALYSIS OF THE NETWORK DYNAMICS OF TRANSFORMING GROWTH FACTOR - ?1 BISTABLE ACTIVATION, WITH IMPLICATIONS ON BISTABILITY AND COMBINATION THERAPY

Abstract

A bistable switch has recently been found to regulate the activation of transforming growth factor-?1 (TGF-?1). An ordinary differential equation (ODE) model was published showing that the net activation of TGF-?1 depends on the balance between two antagonistic sub-pathways. In this thesis, I modeled perturbations that affect both sub-pathways, and simulate how their propagated effects impact the TGF-?1 system. I also studied the behaviour of the model when perturbing individual and pairwise species, and analysed robustness of combination perturbation. I found that factors such as calcium or KLF2, that can affect both the TSP1 sub-pathway and PLS sub-pathway, could have a greatly amplified effect on the feedback behavior of bistable TGF-?1 activation. Combination perturbation analysis suggested that a positive correlation between the synergy of a combination therapy, and the relative robustness of the combination doses, could be a general property of many bistable networks.