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). Although mast cell activation has traditionally been considered an antigen-dependent response mediated via the FcepsilonRI, there is an increasing appreciation that other receptors (and other stimuli) may profoundly influence antigen-mediated degranulation. Furthermore, activating polymorphisms mutations in, and alternatively spliced forms of receptors andor signaling proteins may further modulate these responses. Such polymorphisms associated with disease states, for example mastocytosis may be manifested by exacerbated mast cell-dependent physiology. We wish therefore to explore how polymorphisms or alternatively spliced variants of receptors or signaling proteins may produce a hyperactive phenotype. Furhtermore we wish to identify disease statesclinical populations where hyper-responsive and low-responsive mast cells exist and identify signaling defects. Finally, we wish to explore potential approaches for inhibiting these responses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
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Jensen, Bettina M; Beaven, Michael A; Iwaki, Shoko et al. (2008) Concurrent inhibition of kit- and FcepsilonRI-mediated signaling: coordinated suppression of mast cell activation. J Pharmacol Exp Ther 324:128-38
Jensen, B M; Akin, C; Gilfillan, A M (2008) Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders. Br J Pharmacol 154:1572-82
Jensen, Bettina M; Metcalfe, Dean D; Gilfillan, Alasdair M (2007) Targeting kit activation: a potential therapeutic approach in the treatment of allergic inflammation. Inflamm Allergy Drug Targets 6:57-62