Modeling Extrinsic Apoptosis Regulatory Network Pathways Using A Rules-based Framework

Abstract

We describe a systems approach to combine mathematical modeling and experimental measurement in the study of apoptosis in mammalian cells. The apoptotic signal is an important all-or-nothing mechanism which must be tightly regulated in the cell. Our focus will be on the role of pro and anti-apoptotic proteins in the extrinsic apoptosis signaling pathway leading to the formation of pores at the mitochondrial membrane by BAK and BAX proteins. This network is a prototypical cue-signal-response-feedback pathway of high biomedical importance. Construction of mathematical signal transduction models that recapitulate key features of signaling pathways as they exist in cells is currently very difficult, in large part because few tools are available to assemble, validate and update large dynamical models. We aim to implement novel methodologies based on “rules-based” techniques to allow for a flexible treatment of this complex network model. The calibration of such a model and application to ongoing experimental work in our laboratory is an important aspect of this work. We report our ongoing work on this subject paying particular attention to the rules-based building framework, the calibration steps and the use of experimental data for model calibration and validation.