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. The project focuses on the high affinity receptor for IgE, FcepsilonRI, an MIRR that plays a key role in allergic reactions. A major goal of this project is to build and test detailed models of the early events of cell signaling mediated by this receptor. The mathematical models will be used to analyze experimental data, determine parameter values, design new experiments and test ideas about the roles of specific signaling molecules and their subunits. Mathematical models of signaling cascades are analogous to stable transfectants. In both the model and the transfectant, a small subset of the molecules that participate in the signal cascade are selected for study. The role of both the model and the transfectant is to understand how the selected molecules interact with each other. Components of the initial model, which has been tested extensively and found to be consistent with available data, are the beta and gamma subunits of FcepsilonRI and the tyrosine kinases Lyn and Syk. This model provides the basis for several proposed extensions. The next molecule in the activation pathway, which an extended model will incorporate, is the transmembrane scaffold protein LAT (linker for activation of T cells). Another extension will consider an inhibitory mechanism. Under many conditions the co-aggregation of an MIRR with an inhibitory receptor, FcepsilonRI IIB, reduces cellular responses. Such co-aggregation may be involved in the damping of allergic reactions. The model developed to study FcepsilonRI mediated signaling will be extended to study the inhibitory events triggered by FcepsilonRI - FcgammaRIIB coaggregation. Additional components of the extended model will be FcgammaRIIB, the inositol phosphatase SHIP1, and the cytosolic adapter protein Grb2. The studies in this project are health related, bearing on allergic reactions and their treatment.
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