GGT Targeting Suppresses Mast Cell Activation by IgE and IL-33

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Mast cell activation by IgE or IL-33 elicits powerful inflammatory responses contributing to allergic disease, a significant health burden in need of novel therapies. Cholesterol-lowering statin drugs targeting HMG Co-A reductase (HMGCR) suppress allergic inflammation in some clinical trials, but effects are inconsistent. Our data suggest that this variability is due to statin resistance that can be circumvented by targeting geranylgeranyl transferase (GGT) downstream of HMGCR. Therefore, this application will test the hypothesis that GGT inhibition suppresses mast cell functions induced by IgE and IL-33. Our preliminary data show statins and GGT inhibitors can block mast cell function in vitro and in vivo. The proposed studies include mechanistic investigations of how GGT blockade alters specific Ras family proteins, as well as the effect of GGT inhibition on IL-33-mediated glycolysis. We further include studies of human mast cells and in vivo models that will reveal fundamental insights into mast cell biology and offer translational potential. We have two Specific Aims: Aim 1: We will determine the effects of GGT blockade on IgE signaling, in vitro and in vivo. Aim 2: We will determine the effects of GGT inhibition on IL-33-mediated mast cell function, in vitro and in vivo.