Mobile receptors diffusing over the surface of a cell allow it to sense its environment and respond to it. For many types of receptors, including the multisubunit immune recognition receptors (MIRR), aggregation of these receptors is crucial for the capture of external ligands and mandatory for the turning on or off of cellular responses. This project aims to understand the underlying physical chemistry of receptor aggregation, to use this understanding to develop mathematical models that can predict the time course of aggregate formation, and to relate aggregation states to specific cellular responses. It then aims to construct and test detailed mathematical models of the early events of cell signaling that are initiated when a ligand induces receptors to aggregate. The high affinity receptor for IgE, FceRI, expressed on basophils and stable transfectants, is the model system that will be used to study signaling mediated by MIRR. The mathematical models will be used to analyze experimental data; determine parameter values; design new experiments; and test ideas about the roles of the beta and gamma subunits of the receptor, and the tyrosine kinases Lyn and Syk. Cytokines induce receptor aggregation in a quite different way than the MIRR. The interaction of IL-2 with its receptor subunits will be studied using novel soluble multichain constructs. Estimates of rate constants for both receptor systems will be obtained from binding studies using the BIAcore biosensor.
An aim of this project is to develop methods to use the BlAcore to study ligand-induced receptor aggregation. The studies in this project are health related, bearing on allergic reactions and their treatment as well as other aspects of the immune response.
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