The binding of a ligand to a cell surface receptor is the first step in a cascade of events that leads to the generation of a transmembrane signal. In many cell systems, simple ligand binding is insufficient to initiate signal transduction, rather, receptor aggregation is required. On the surface of mast cells, basophils and rat basophilic leukemia (RBL) cells are Fc receptors (FcepsilonRI) which bind IgE with high affinity. The formation of aggregates of IgE, or equivalently of the FcepsilonRI receptors, triggers various cellular responses. However, it is not clear what physical and steric conditions must be met by the IgE-receptor aggregates in order to initiate signal transduction. The goal of this project is to understand receptor aggregation in general and in particular to determine the properties of an aggregate that lead to specific responses. To do this we have developed an approach based on multiparameter flow cytometry to measure the kinetics of ligand binding and crosslinking of cell surface IgE. This method allows us to develop a quantitative picture of the aggregation states induced by multivalent-antigen binding to sIgE. We will develop and test mathematical models that predict the time course of the IgE aggregate distribution that is formed when surface IgE is crosslinked by these ligands and relate this aggregation to cellular responses including early (phosphorylation of tyrosines), middle (calcium fluxes), and late (degranualtion) events in the signal transduction cascade. We expect that the results of these studies can be generalized to other receptor systems in which receptor aggregation is involved in signal transduction. The studies in this project are health related bearing on allergic reactions as well as ligand receptor reactions in general.
| Colvin, Joshua; Monine, Michael I; Gutenkunst, Ryan N et al. (2010) RuleMonkey: software for stochastic simulation of rule-based models. BMC Bioinformatics 11:404 |
| Monine, Michael I; Posner, Richard G; Savage, Paul B et al. (2010) Modeling multivalent ligand-receptor interactions with steric constraints on configurations of cell-surface receptor aggregates. Biophys J 98:48-56 |
| Colvin, Joshua; Monine, Michael I; Faeder, James R et al. (2009) Simulation of large-scale rule-based models. Bioinformatics 25:910-7 |
