Mast cells play a pivotal role in the pathogenesis of asthma and other allergic diseases. These reactions are generally initiated by antigen-dependent aggregation of the high affinity IgE receptor (Fc-epsilon-RI) expressed on the cell surface and subsequent release of pro-inflammatory mediators (e.g. histamine, prostanoids, proteases and cytokines). We have demonstrated that interferon-gamma up-regulates the high affinity receptor for IgG (Fc-gamma-RI) on cultured human mast cells and that aggregation of these receptors through IgG leads to mast cell mediator release. Furthermore, Fc-epsilon-RI mediated responses are potentiated by stem cell factor (SCF) following binding to its receptor, Kit. The signaling pathways linking Fc aggregation to human mast cell activation have yet to be fully delineated. In addition, how Kit modifies these Fc-mediated signaling events is unclear. Thus the primary focus of the research is the elucidation of signaling mechanisms associated with the activation of human mast cells via the Fc-epsilon-RI, the Fc-gamma-RI and the Kit receptor. The goal is to identify new therapeutic targets in the treatment of allergic diseases. We have observed that Fc-epsilon-RI, Fc-gamma-RI, and Kit mediated unique and convergent signals for the release of inflammatory mediators from human mast cells. This allows not only similarities and differnces in the mediators released by the aggregation of Fc-epsiolon-RI and Fc-gamma-RI but also allows Kit to enhance Fc-epsilon-RI mediated responses without inducing degranulation on its own. Thus we are investigating common and distinct signaling events regulated by these receptors in mast cells. Recent studies have focused on the roles of PI-3 kinase isoforms and a novel adaptor molecule, NTAL, in these events. The studies conducted in human mast cells have recently been expanded to look at the roles of specific molecules in the activation of mast cells derived from the bone marrow of knock out / transgenic mice in combination with siRNA approaches in both human and mouse mast cells.
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