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

IgE或IL-33激活肥大细胞可引起强烈的炎症反应 过敏性疾病是严重的健康负担，需要新的治疗方法。降胆固醇 靶向HMG Co-A还原酶(HMGCR)的他汀类药物抑制部分患者的变态反应性炎症 临床试验，但效果不一致。我们的数据表明，这种差异是由于他汀类药物造成的 通过靶向香叶基香叶基转移酶(GGT)下游可以规避的耐药性 HMGCR。因此，这一应用程序将检验GGT抑制抑制的假设 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GGT 在体外和体内，抑制剂都可以阻断肥大细胞的功能。建议的研究包括 GGT阻断如何改变特定的RAS家族蛋白以及 GGT抑制对IL-33介导的糖酵解的影响我们还包括对人类的研究 肥大细胞和体内模型，将揭示肥大细胞生物学和 提供翻译潜力。我们有两个具体目标： 目的1：体外和体内研究GGT阻断对IgE信号转导的影响。 目的2：研究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.