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Center for Nonlinear Studies |
The cellular response to allergens is initialized with the formation of cell-surface receptor aggregates and propagated via an intracellular signaling network. Signal transduction culminates in the release of chemical mediators into the local environment (a process known as degranulation). To study this phenomenon in vivo, the multivalent ligand DNP-BSA is commonly used to stimulate aggregation using anti-DNP IgE bound to the FcεRI transmembrane receptor. Prior work has aimed to characterize receptor aggregation formally, but the inherent combinatorial complexity in representing dynamical systems involving multivalent molecules typically results in simplified models. In this work, we use rule-based modeling techniques to overcome this barrier, building a mechanistic model of the DNP-BSA-IgE interaction without disregarding complex phenomena, such as the formation of ring-like structures and size-limited mobility of receptor aggregates. In parallel, we are developing a model of the early intracellular signaling events involving FcεRI and its intracellular constituents, the kinases Lyn and Syk. Recent work has shown that a mutant form of Syk reduces the mean lifetime of Syk recruitment by a factor of two, but completely inhibits the degranulation response. We expect that the dynamics of this system together with novel Syk-FcεRI interaction mechanisms will explain the inhibitory effect of such a small difference in the lifetime of membrane localization. Coupling these two models should elucidate the relationship between cellular response and ligand configuration/dose, enabling prediction of how distinct distributions of receptor aggregates form and induce signaling based on properties of the allergen.
Host: Chris Neale