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Alenazy, Leila

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Alenazy

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Leila

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Alenazy, Leila

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    Phosphatases in Mouse Mast Cell Rapid IgE Desensitization: The Role of SHIP-1
    (2017-06-07) Alenazy, Leila; Castells, Mariana; Austen, K. Frank
    Rapid Drug Desensitization (RDD) is a widely used and effective clinical approach to enable allergic individuals to temporary tolerate various drugs to which they have an IgE-mediated hypersensitivity reaction. Latest studies have found mast cells (MCs) as the primary target cells for Desensitization (DS). Studies on both in vitro and in vivo murine rapid IgE/MCs DS showed impairment of all MC activation hallmarks such as receptor internalization, calcium mobilization, degranulation, production of lipid mediators and cytokines. However, the molecular targets and underlying mechanisms behind this process remain unclear. Previous studies have shown that the inositol phosphatase SHIP acts as a “gatekeeper” and negatively regulate MC degranulation over all antigen doses. Thus, we hypothesize that the multiple subthreshold doses of antigen during DS might result in recruitment of SHIP-1. Here, we focused on assessing the role of phosphatases specifically SHIP-1 in FcεRI signal regulation during DS. We have used SiRNA and SHIP-1 inhibitor, 3-a-aminocholestane (3AC) to knock down (KD) the protein expression and inhibit its biological activity respectively. Our preliminary data showed more degranulation response at the end of the DS in SHIP-1 KD BMMCs compare to the WT BMMCs, indicating an inhibitory response of SHIP-1. Although 3AC at a range of concentrations between 2 to 100M did not shown an inhibitory response, we found more phospho-SHIP1 in the early steps of DS compare to later steps; indicating its critical role in turning the inhibitory pathway. Our future direction is to measure other parameters of MCs activation such as Ca+2 flux, receptor internalization, lipid mediators and cytokine production. In addition, we intend to replicate the DS protocol in RBL cells (an adherent MCs) to visualize SHIP-1 co-localization with FcRI during DS.