EARLY EVENTS IN MAST CELL SIGNALING

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 FCepsilonRI receptors that bind IgE with high affinity. The formation of aggregates of IgE-FCepsilonRI complexes triggers various cellular responses. The aim of this project is to understand receptor aggregation in general and in particular to determine the properties of IgE-FCepsilonRI aggregates that initiate specific cellular responses. We will use spectroscopic techniques to perform binding studies with ligands that can crosslink sIgE and simultaneously measure cellular responses (calcium transients, degranualtion, tyrosine phosphorylation) Using mathematical models we hope to draw conclusions about the state of receptor clustering and its relation to cell signaling, Our goal is to promote a stronger understanding of the earliest events that lead to mast cell stimulation. 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.