Critical signaling nodes regulating mast cell releasibility phenotypes

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。这些反应通常是由表达在细胞表面的高亲和力IgE受体（Fc-epsilon-RI）的抗原依赖性聚集和随后的促炎介质（如组胺、类二十烷酸、蛋白酶和细胞因子）的释放引起的。我们希望确定肥大细胞活化表型在健康和疾病中是如何调节的，确定疾病状态和临床人群中存在高反应性和低反应性肥大细胞表型，并确定导致这些表型的特定信号缺陷。除了Fc-epsilon-RI外，越来越多的人认识到其他受体（和其他刺激）可能深刻影响抗原介导的脱颗粒。激活受体和/或信号蛋白的多态性/突变和选择性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性，如过敏反应、特应性反应和肥大细胞增多症，可能表现为肥大细胞依赖性生理加剧。因此，我们也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性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 how the mast cell activation phenotype is regulated in health and disease, to identify disease states and clinical populations where hyper-responsive and hypo-responsive mast cell phenotypes exist and to identify specific signaling defects responsible for these phenotypes. In addition to the Fc-epsilon-RI, 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, like anaphylaxis, atopy, and 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. The following observations were made since the last report: i. Stem cell factor and other critcal cytokines program the mast cell activation phenotype We identified a novel mechanism for the regulation of the extent of mast cell activation through SCF-dependent induction of a hypo-responsive phenotype with respect to both cytokine production and degranulation. This phenotype was not due to down-regulation of the expression of either Fc-epsilon-RI or KIT, but could be explained by an inability of the cells to undergo the cytoskeletal reorganization required for mediator release, potentially as a consequence of decreased expression of the Src kinase Hck. These findings revealed that the sensitivity of mast cells to IgE/antigen stimulation is highly regulated by SCF and, as recently discoverd, other cytokines in the surrounding tissue milieu and may thus have important implications for understanding how the activation capacity of tissue mast cells may be phenotypically modified in health and in disease. 2. Hyperactive/hyperproliferatve mast cell phenotype Mast cells are generated from peripheral blood progenitors from patients and a subset of these mast cells appear to have a hyper-proliferative, hyper-responsive phenotype. These features may be linked to exaggerated antigen-mediated signaling processes and the potential genes underlying these phenotypes are being investigated.