The molecular mechanisms that govern cell growth and division has been the subject of intense interest for the past two decades. A large body of literature exists explaining in molecular detail the biochemical activity of the proteins involved in cell cycle regulation. Further, some progress has been made in understanding the interaction of individual components of this system with one another. What is lacking is a theoretical framework for studying the operation of the cell cycle as a complete system rather than as a few isolated components at a time. The purpose of the work described in this proposal is to develop a mathematical model that incorporates all major protein reactions through the full cell cycle, that contains relevant parameter values, that reproduces known experiments, and that makes experimentally testable predictions. Because this model will allow us to understand multiple variables at a time, it will provide a promising tool for guiding future experiments as well as predicting the outcomes of treatments for human disorders, like cancer, that are based on cell cycle components. Currently, known parameter values for important cell cycle components are either unknown, or are obtained from varying experimental systems using different conditions. This precludes accurate mathematical modeling. First, we will obtain all necessary parameter values from a mouse embryonic fibroblast (MEF) experimental system using consistent experimental conditions. These parameter values will be used to improve current models of specific cell cycle phases. Second, we will perform experiments to test specific predictions and assumptions of these phase-specific models. The results of these studies will establish the reliability of the models, or suggest ways to improve them. Third, that phase specific models will be integrated into a more complete cell cycle model, with known parameter values restricted to MEF cells, that will model the interactions of the major proteins that regulate the cell cycle through G1, S, G2 and M phases. By successive iterations of experiment and mathematical analysis, this model can be refined to simulate known experimental behavior of the MEF cell cycle.
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