Modeling and Parameter Estimation for Heterogeneous Cell Populations

Most of the modeling performed in biology aims at achieving a quantitative description and understanding of the intracellular signaling pathways within a "typical cell." However, in many biologically important situations even genetically identical cell populations show a heterogeneous response. This means that individual members of the cell population behave differently. Such situations require the study of cell-to-cell variability and the development of models for heterogeneous cell populations. The main contribution of this thesis is the development of unifying modeling frameworks for signal transduction and proliferation processes in heterogeneous cell populations. These modeling frameworks allow for the detailed description of individual cells as well as differences between them. In contrast to many existing modeling approaches, the proposed frameworks allow for a direct comparison of model predictions with available data. Beyond this, the proposed population models can be simulated efficiently and, by exploiting the model structures, we are able to develop model-tailored Bayesian parameter estimation methods. These methods enable the calculation of the optimal parameter estimates, as well as the evaluation of the parameter and prediction uncertainties. The proposed tools allow for novel insights in population dynamics, in particular the model-based characterization of population heterogeneity and cellular subgroups. This is illustrated for two different application examples: pro- and anti-apoptotic signaling, which is interesting in the context of cancer therapy, and immune cell proliferation.