The Function of SWAP-70 in Mast Cells

SWAP-70 在肥大细胞中的功能

• 批准号: 6733560
• 负责人: ROLF JESSBERGER
• 金额: $ 29.66万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6733560
• 关键词: DNA binding protein; antibody receptor; biological signal transduction; exocytosis; genetically modified animals; laboratory mouse; mast cell; nucleoproteins; phosphorylation; protein structure function

DESCRIPTION (provided by applicant): Mast cells play diverse and important roles in the mammalian immune system. Upon aggregation of the Fc-epsilonRI receptor, mast cells can degranulate and release histamine and other biologically active compounds. While beneficial in some instances, e.g. within the innate immune system, such reactions are also causing allergic reactions, including asthma and anaphylaxis. Aberrant proliferation of mast cells characterizes many mast cell tumors. Details of the signaling pathways that trigger mast cell degranulation need to be further defined. Protein SWAP-70, identified by us earlier from B cells, has signatures of a novel type of signal transducing protein, and is also expressed in mast cells. Mast cells derived from our recently generated SWAP-70 -/- mice show impaired Fc-epsilonRI-triggered degranulation. This proposal suggests an important contribution of protein SWAP-70 to mast cell biology, i.e. exocytosis. Specifically, we hypothesize that SWAP-70 through its newly determined Rac-specific guanosine nucleotide exchange activity is important for Fc-epsilonRI-triggered exocytosis in mast cells. Therefore, we aim at understanding the role and position of SWAP- 70 in the signaling pathway leading to Fc-epsilonRI-triggered exocytosis, and will explore how SWAP-70 itself is regulated. Towards this goal, we will apply a combination of biochemical and cellular approaches. The proposed experiments should yield key information on pathways regulating mast cell exocytosis, and will help understanding mast cell-associated diseases such as allergic reactions.

描述（由申请人提供）：肥大细胞在哺乳动物免疫系统中起多种和重要作用。 FC- EPSILONRI受体聚集后，肥大细胞会脱脂并释放组胺和其他具有生物活性的化合物。虽然在某些情况下有益，例如在先天免疫系统中，这种反应也引起过敏反应，包括哮喘和过敏反应。肥大细胞的异常增殖表征了许多肥大细胞肿瘤。需要进一步定义触发肥大细胞脱粒的信号通路的详细信息。蛋白质SWAP-70，由我们早些时候从B细胞中鉴定出来，具有新型信号转导蛋白的特征，并且在肥大细胞中也表达。源自我们最近生成的swap-70 - / - 小鼠的肥大细胞显示出受损的FC- epsilonri触发的脱粒。该建议表明，蛋白质交换-70对肥大细胞生物学的重要贡献，即胞吐作用。具体而言，我们假设Swap-70通过其新确定的RAC特异性鸟苷核苷酸交换活性对于肥大细胞中FC- epsilonri触发的胞吐作用很重要。因此，我们的目的是了解交换70在导致FC- epsilonri触发的胞吐作用的信号传导途径中的作用和位置，并将探讨如何调节交换-70本身。为了实现这一目标，我们将采用生化和细胞方法的结合。提出的实验应产生有关调节肥大细胞胞吐作用的途径的关键信息，并将有助于理解与肥大细胞相关疾病（例如过敏反应）。