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). However, we have demonstrated that ligands for other receptors such as Kit may serve to prime mast cells for, or act as co-activators of, antigen-mediated mast cell activation. The signaling pathways linking Fc-epsilon-RI aggregation to human mast cell activation and function and how other receptors modify 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 mast cells via the Fc-epsilon-RI and especially how the signaling pathways initiated by other receptors may integrate with those initiated by the Fc-epsilon-RI for synergistic mast cell activation and/or inhibition.? ? 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 differences in the mediators released by the aggregation of Fc-epsilon-RI and Fc-gamma-RI but also allows Kit to enhance Fc-epsilon-RI mediated responses without inducing degranulation on its own. Recent studies have focused on the roles of PI 3-kinase, the adaptor molecule, NTAL, and the tyrosine kinase Btk in these evenets. 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 and shRNA approaches in both human and mouse mast cells.

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National Institute of Allergy and Infectious Diseases (NIAID)
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