Critical signaling nodes regulating mast cell releasibility phenotypes

调节肥大细胞释放表型的关键信号节点

• 批准号: 8555901
• 负责人: Dean D Metcalfe
• 金额: $ 32.24万
• 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/8555901
• 关键词: Affinity; Allergic Disease; Anaphylaxis; Antigens; Asthma; Cell surface; Cells; Clinical; Cytoskeletal Modeling; Defect; Disease; Down-Regulation; Eicosanoids; Fc epsilon RI; Genes; Genetic Polymorphism; Goals; Health; Histamine; IgE; IgE Receptors; Inflammation Mediators; Link; Mediating; Mediator of activation protein; Mutation; Pathogenesis; Patients; Peptide Hydrolases; Phenotype; Physiology; Play; Population; Process; Production; Protein Isoforms; RNA Splicing; Reaction; Receptor Signaling; Regulation; Reporting; Role; Signal Transduction; Signaling Protein; Stem Cell Factor; Stimulus; Tissues; Variant; atopy; base; computerized data processing; cytokine; mast cell; mastocytosis; novel; peripheral blood; progenitor; programs; receptor; response; src-Family Kinases

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.

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、类花生酸、蛋白酶和细胞因子）的释放引发。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，以确定存在高反应性和低反应性肥大细胞表型的疾病状态和临床人群，并确定负责这些表型的特定信号传导缺陷。除了Fc-γ-RI之外，越来越多的人认识到其他受体（和其他刺激物）可能深刻地影响抗原介导的脱粒。受体和/或信号传导蛋白中的激活多态性/突变以及受体和/或信号传导蛋白的选择性剪接形式可以进一步调节这些应答。这种与疾病状态相关的多态性，如过敏反应、特应性和肥大细胞增多症，可能表现为肥大细胞依赖性生理学的恶化。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可变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。 自上次报告以来，提出了以下意见： I.干细胞因子和其他关键细胞因子编程肥大细胞活化表型 我们确定了一种新的机制，通过SCF依赖性诱导低反应表型的细胞因子的产生和脱粒的调节肥大细胞活化的程度。这种表型不是由于下调表达的Fc-γ-RI或KIT，但可以解释为细胞无法进行所需的介质释放的细胞骨架重组，可能是由于减少表达的Src激酶Hck。这些研究结果表明，肥大细胞对IgE/抗原刺激的敏感性受到SCF的高度调节，最近发现，周围组织环境中的其他细胞因子也受到调节，因此可能对理解组织肥大细胞的活化能力如何在健康和疾病中表型改变具有重要意义。 2.肥大细胞过度活跃/过度增殖表型 肥大细胞由患者的外周血祖细胞产生，并且这些肥大细胞的子集似乎具有过度增殖、过度反应表型。这些特征可能与夸大的抗原介导的信号传导过程有关，这些表型的潜在基因正在研究中。

项目成果

Generation, isolation, and maintenance of human mast cells and mast cell lines derived from peripheral blood or cord blood.

• DOI: 10.1002/0471142735.im0737s90
• 发表时间: 2010-08-01
• 期刊: Current protocols in immunology
• 作者: Radinger, Madeleine;Jensen, Bettina M;Gilfillan, Alasdair M
• 通讯作者: Gilfillan, Alasdair M

Regulation of mast cell responses in health and disease.

• DOI: 10.1615/critrevimmunol.v31.i6.30
• 发表时间: 2011
• 期刊: Critical reviews in immunology
• 影响因子: 1.3
• 作者: Gilfillan AM;Beaven MA
• 通讯作者: Beaven MA

Mechanisms of mast cell signaling in anaphylaxis.

• DOI: 10.1016/j.jaci.2009.08.035
• 发表时间: 2009-10
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Metcalfe, Dean D.;Peavy, Richard D.;Gilfillan, Alasdair M.
• 通讯作者: Gilfillan, Alasdair M.