Identification of Critical Signaling Pathways Modulating Mast Cell Activation

肥大细胞在哮喘和其他过敏性疾病的发病机制中起着关键作用。这些反应通常由细胞表面上表达的高亲和力IgE受体（Fc-IgE-RI）的抗原依赖性聚集和随后促炎介质（例如组胺、前列腺素类、蛋白酶和细胞因子）的释放引发。然而，其他受体如KIT和各种GPCR的配体可用于引发肥大细胞进行抗原介导的肥大细胞活化或充当抗原介导的肥大细胞活化的共活化剂。将Fc-γ-RI聚集与人肥大细胞活化和功能联系起来的信号传导途径以及其他受体如何修饰这些Fc介导的信号传导事件尚不清楚。因此，研究的主要焦点是阐明与通过Fc-γ-RI活化肥大细胞相关的信号传导机制，特别是由其他受体引发的信号传导途径如何与Fc-γ-RI引发的信号传导途径整合，以协同肥大细胞活化和/或抑制。 肥大细胞在体内影响疾病状态的能力还取决于它们从它们的祖细胞的生长和分化、肥大细胞向它们的驻留组织的迁移以及在这些位点的存活。因此，整合的受体介导的信号事件调节这些过程也正在研究。

Mast cells play a pivotal role in the pathogenesis of asthma and other allergic diseases. These reactions are generally initiated by antigen-dependent aggregation of the high affinity IgE receptor (Fc-epsilon-RI) expressed on the cell surface and subsequent release of pro-inflammatory mediators (e.g. histamine, prostanoids, proteases and cytokines). However, ligands for other receptors such as KIT and various GPCRs may serve to prime mast cells for, or act as co-activators of, antigen-mediated mast cell activation. The signaling pathways linking Fc-epsilon-RI aggregation to human mast cell activation and function and how other receptors modify these Fc-mediated signaling events is unclear. Thus the primary focus of the research is the elucidation of signaling mechanisms associated with the activation of mast cells via the Fc-epsilon-RI and especially how the signaling pathways initiated by other receptors may integrate with those initiated by the Fc-epsilon-RI for synergistic mast cell activation and/or inhibition. The ability of mast cells to impact disease states in vivo also depends on their growth and differentiation from their progenitor cells, migration of the mast cells to their resident tissues, and survival at these sites. Therefore the integrated receptor-mediated signaling events regulating these processes are also being examined.