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

IgE或IL-33对肥大细胞的激活引发了强有力的炎症反应， 过敏性疾病是一种需要新疗法的重大健康负担。降胆 靶向HMG Co-A还原酶（HMGCR）他汀类药物抑制某些过敏性炎症 临床试验，但效果不一致。我们的数据表明，这种变异性是由于他汀类药物 可以通过靶向下游的香叶基香叶基转移酶（GGT） 关于HMGCR因此，本申请将检验GGT抑制抑制 由IgE和IL-33诱导的肥大细胞功能。我们的初步数据显示他汀类药物和谷氨酰转肽酶 抑制剂可以在体外和体内阻断肥大细胞功能。拟议的研究包括 GGT阻断如何改变特定Ras家族蛋白的机制研究，以及 GGT抑制对IL-33介导的糖酵解的影响。我们进一步包括人类的研究 肥大细胞和体内模型，将揭示肥大细胞生物学的基本见解， 提供翻译潜力。我们有两个具体目标： 目的1：我们将在体外和体内确定GGT阻断对IgE信号传导的影响。 目的2：我们将确定GGT抑制对IL-33介导的肥大细胞功能的影响， 体外和体内。

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.