Mast cells have high proinflammatory potential because they contain a large number of bioactive mediators of three classes: preformed, secretory granule-derived mediators such as histamine and proteases; newly generated lipid mediators such as leukotriene C4 (LTC4), prostaglandin D2, and the platelet-activating factor; and a panoply of proinflammatory cytokines including IL-1B, IL-6, and TNF-a. Mast cells, which reside in normal tissues at the interface between self and non-self, must be tightly regulated to prevent the deleterious effects of innate or immunologic activation. Indeed, inappropriate activation of mast cells leads to immediate hypersensitivity reactions and bronchial asthma. The investigator has discovered and characterized the mouse mast cell gp49 gene family, which is part of the Immunoglobulin Superfamily. The cytoplasmic domain of one member of the family, gp49B1, contains two Immunoreceptor Tyrosine-based Inhibition Motifs (ITIMs). He showed that the cross-linking of gp49B1 with the high affinity IgE receptor (FceRI) on mast cells inhibits the exocytosis of histamine and B-hexosaminidase, as well as the generation of LTC4. Thus, gp49B1 is a newly recognized counter-regulator of mast cell activation. However, the mechanism(s) by which gp49B1 inhibits mast cell activation is known, as is the natural ligand for gp49B1 (""""""""gp49B1L""""""""). The broad objective of the proposed research is to understand more about the cellular and molecular biology of gp49B1 in mast cells, with the long range goal of harnessing its ligand-driven inhibitory pathway to control deleterious mast cell activation that causes allergic reactions and contributes to the pathogenesis of bronchial asthma and other forms of inflammation. The application proposes to achieve the first stage of its broad objective by pursuing the following Specific Aims: 1) to define the molecular mechanism(s) by which gp49B1 inhibits the signal transduction pathways leading to mast cell activation; and 2) to clone, characterize, and express gp49B1L so as to define the biologic significance of its interaction with gp49B1.
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