Mechanisms and regulation of IgE-dependent mast cell activation.

Allergic diseases such as asthma, rhinitis or atopic dermatitis have reached epidemic proportions worldwide. Mast cells play a central role in allergic inflammation. This is because allergen binding on mast cells initiates a cascade of signaling events leading to excessive secretion of biologically potent mast cell mediators. Accordingly, understanding of mechanisms involved in controlling mast cell mediator secretion is essential for the development of effective therapy for the treatment of allergy and asthma. Calcineurin is an intracellular enzyme that has three different isoforms with different functions. The contributions of these specific calcineurin isoforms in the development of allergy have not been reported previously. In contrast, several pharmaceutical "calcineurin inhibitors" have been used clinically for the treatment of allergic disorders such as atopic dermatitis, chronic urticaria and asthma based on their pharmacological effects. Some of these inhibitors have serious side effects. Recent studies questions whether "calcineurin inhibitors" work through calcineurin. This highlights the need of more definitive studies on the contribution of calcineurin (and the isoforms) in the regulation of mast cell-involved allergic inflammation. We will use biochemical and genetic approaches (1) to investigate the role of calcineurin isoforms in the regulation of mast cell signal transduction and mediator production, (2) to determine the significance of calcineurin isoforms in the development of asthma.