Activation of Mast Cells in Disease States: Pharmacological Modification

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)的抗原依赖性聚集和随后释放的促炎介质(如组胺、二十烷类化合物、蛋白酶和细胞因子)启动的。我们希望确定存在高反应性和低反应性肥大细胞的疾病状态和临床人群，并确定导致这些表型的特定信号缺陷。除了FcepsilonRI，人们越来越认识到，其他受体(和其他刺激)可能会深刻地影响抗原介导的脱颗粒。激活受体和/或信号蛋白的多态/突变或剪接形式可能会进一步调节这些反应。这种与疾病状态相关的多态，例如肥大细胞增多症，可能表现为加重的肥大细胞依赖生理学。因此，我们还希望探索其他肥大细胞受体在疾病状态中的作用，以及受体或信号蛋白的多态或选择性剪接变体如何产生过度活跃的表型。最后，我们希望探索抑制这些反应的潜在方法。

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, eicosanoids, proteases and cytokines). We wish to identify disease states and clinical populations where hyper-responsive and low-responsive mast cells exist and to identify specific signaling defects responsible for these phenotypes. In addition to the FcepsilonRI, there is an increasing appreciation that other receptors (and other stimuli) may profoundly influence antigen-mediated degranulation. Activating polymorphisms/mutations in, and alternatively spliced forms of receptors and/or signaling proteins may further modulate these responses. Such polymorphisms associated with disease states, for example mastocytosis, may be manifested by exacerbated mast cell-dependent physiology. We wish therefore to also explore the role of other mast cell receptors in disease states and how polymorphisms or alternatively spliced variants of receptors or signaling proteins may produce a hyperactive phenotype. Finally, we wish to explore potential approaches for inhibiting these responses.