Construction and analysis of a modular model of caspase activation in apoptosis

A model of caspase activation is constructed and analyzed. The apoptosis signaling network is simplified through modularization methodologies and equilibrium abstractions for three functional modules. The mathematical model is composed of a system of ordinary differential equations which is numerically solved. Multiple linear regression analysis investigates the role of each module and reduced models are constructed to identify key contributions of the extrinsic and intrinsic pathways in triggering apoptosis for different cell lines.Through linear regression techniques, we identified the feedbacks, dissociation of complexes, and negative regulators as the key components in apoptosis. The analysis and reduced models for our model formulation reveal that the chosen cell lines predominately exhibit strong extrinsic caspase, typical of type I cell, behavior. Furthermore, under the simplified model framework, the selected cells lines exhibit different modes by which caspase activation may occur. Finally the proposed modularized model of apoptosis may generalize behavior for additional cells and tissues, specifically identifying and predicting components responsible for the transition from type I to type II cell behavior.Apoptosis, or programmed cell death, is a highly regulated cell death mechanism involved in many physiological processes including development, elimination of damaged cells, and immune response [1-9]. Dysregulation of apoptosis is associated with pathological conditions such as developmental defects, neurodegenerative disorders, autoimmune disorders, and tumorigenesis [10-16]. The apoptotic pathway is characterized by complex interactions of a large number of molecular components which are involved in the induction and execution of apoptosis. Although scientists do not fully understand the entire pathway, key characteristics have been identified which motivates further study of this cellular process.As summarized in Figure 1, apoptosis is a cell suicide m