Identification of Critical Signaling Pathways Modulating Mast Cell Activation

调节肥大细胞激活的关键信号通路的鉴定

• 批准号: 8175272
• 负责人: Dean D Metcalfe
• 金额: $ 36.48万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8175272
• 关键词: Affinity; Allergic Disease; Antigens; Asthma; Cell surface; Cellular biology; Differentiation and Growth; Disease; Event; Fc Receptor; Fc epsilon RI; Histamine; Human; IgE; Inflammation Mediators; Ligands; Link; Mediating; Mediator of activation protein; Pathogenesis; Peptide Hydrolases; Play; Process; Prostaglandins; Reaction; Research; Role; Signal Pathway; Signal Transduction; Site; Stem cells; Tissue Survival; cell motility; cytokine; in vivo; mast cell; receptor; receptor-mediated signaling

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.

肥大细胞在哮喘和其他过敏性疾病的发病机制中发挥着关键作用。这些反应通常是由细胞表面表达的高亲和力 IgE 受体 (Fc-epsilon-RI) 的抗原依赖性聚集以及随后促炎介质（例如组胺、前列腺素、蛋白酶和细胞因子）的释放引发的。然而，其他受体（例如 KIT 和各种 GPCR）的配体可用于启动肥大细胞，或充当抗原介导的肥大细胞激活的共激活剂。将 Fc-ε-RI 聚集与人类肥大细胞激活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，该研究的主要焦点是阐明与通过 Fc-epsilon-RI 激活肥大细胞相关的信号传导机制，特别是其他受体启动的信号传导途径如何与 Fc-epsilon-RI 启动的信号传导途径整合以协同肥大细胞激活和/或抑制。 肥大细胞影响体内疾病状态的能力还取决于它们的生长和从祖细胞的分化、肥大细胞向其驻留组织的迁移以及在这些部位的存活。因此，调节这些过程的整合受体介导的信号事件也正在受到检查。