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

GGT 靶向抑制 IgE 和 IL-33 激活肥大细胞

• 批准号: 9794165
• 负责人: John J Ryan
• 金额: $ 6.77万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794165
• 关键词: Address; Allergic Disease; Allergic inflammation; Antibodies; Cell physiology; Cellular biology; Cholesterol; Clinical Trials; Complex; Data; Drug Targeting; Drug resistance; Glycolysis; Health; Human; IgE; Immune response; In Vitro; Inflammation; Inflammatory Response; Investigation; KRAS2 gene; Link; Lung diseases; Mediating; Oxidoreductase; Pathway interactions; Pharmaceutical Preparations; Protein Family; Protein Isoforms; Proto-Oncogene Protein c-kit; Resistance; Signal Transduction; Testing; cytokine; in vivo; in vivo Model; inhibitor/antagonist; insight; isoprenoid; mast cell; novel therapeutics; protein geranylgeranyltransferase; response

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.

通过IgE或IL-33激活肥大细胞，引起有力的炎症反应 过敏性疾病，这是需要新疗法的重大健康负担。降胆固醇 针对HMG Co-A还原酶（HMGCR）的他汀类药物抑制某些人的过敏性炎症 临床试验，但影响不一致。我们的数据表明，这种可变性是由于他汀类药物引起的 可以通过靶向下游的黄烷基转移酶（GGT）来规避的抗性 HMGCR。因此，该应用将测试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了他汀类药物和GGT 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封锁如何改变特定RAS家族蛋白的机械研究以及 GGT抑制对IL-33介导的糖酵解的影响。我们进一步包括对人类的研究 肥大细胞和体内模型将揭示对肥大细胞生物学和 提供翻译潜力。我们有两个具体的目标： 目标1：我们将确定GGT阻断对IgE信号，体外和体内的影响。 目标2：我们将确定GGT抑制对IL-33介导的肥大细胞功能的影响， 体内和体内。