March 24, Tue 2015
1:00 pm, MRB 100C
Dr. Carlos Lopez
Assistant Professor of Cancer Biology, Vanderbilt University
Use of biological model-programs in PySB to explore and calibrate cell-death decisions
Programmed necrosis (a.k.a. necroptosis) has recently been discovered as a programmed cell-death alternative to apoptosis. Death receptor mediated signaling can induce either apoptotic or necroptotic cell death, through a complex biochemical network machinery, and thus represents an ideal system to understand molecular mechanisms associated with cell-decision processes. In this work we show how novel mathematical modeling approaches using our PySB language can be used to instantiate multiple mechanistic hypotheses. These can then be calibrated to experimental data, using a Bayesian-inference approach, to explore multiple mechanistic hypotheses about apoptosis or necroptosis outcomes. We test multiple model execution hypotheses and find viable mechanisms that are then validated through experiments. In particular our simulations and analysis suggest that the core decision-making machinery for apoptosis or necroptosis seems to depend on the relative concentrations and interactions among the Rip1, Caspase 8, and Bid proteins rather than a single protein. Our findings underscore the need for systems-level evaluation of multiple mechanisms in molecule-driven cell-decision processes.