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.
Mast cell activation by factors such as IgE antibodies and the cytokine IL-33 occurs early in many immune responses, and is a central factor in some pulmonary diseases. Our data show that cholesterol-lowering statin drugs are powerful suppressors of mast cell function, but that drug resistance is common. We find that statin effects are actually due to loss of geranylgeranyl transferase (GGT) function, and that GGT antagonism reliably inhibits mast cell function. This application will determine how GGT inhibition disrupts mast cell-mediated responses and how this can be accomplished in vivo
