Regulation of FcεRI function by the MS4A gene cluster

项目摘要 过敏性疾病如哮喘、特应性皮炎和食物过敏共同影响30 - 40%的成年人， 美国的儿童，他们的患病率正在上升。目前的治疗策略通常依赖于 中和单独的介质和/或抑制免疫应答。然而，针对单一介质 在炎症反应中，仅去除一部分炎症介质"池"， 直接和特异性靶向炎性肥大细胞的治疗是一种未满足的需求。所有过敏性疾病 具有改变肥大细胞表型的共同特征，导致促炎性细胞因子慢性分泌过多， 肥大细胞介质如组胺、5-羟色胺、白细胞三烯、白藜芦醇、蛋白酶和细胞因子。是 可能遗传的遗传特征和环境/表观遗传改变在 这种过敏性肥大细胞表型的发展。有趣的是，人类连锁分析已经确定， 基因座11q12-q13与过敏和哮喘易感性密切相关。 跨膜（MS）4A基因簇编码人类中至少16个基因的家族， 在免疫细胞中表达。目前的证据表明MS4A家族与相关疾病之间存在联系。 有炎症整个MS4A基因簇位于11q12-q13之间，表明与过敏症存在潜在联系。 在这个应用中，我们提出，MS4A基因簇在一个超- 反应性肥大细胞表型。目前，这些基因中只有两个被详细研究， 在免疫细胞信号传导和功能中的重要作用。在这项研究中，我们将建立MS4A基因的作用， 在人类肥大细胞功能中进行聚类，并将MS4A蛋白鉴定为Fc ε RI运输的新型调节剂， 定义人肥大细胞功能的信号传导和对来自非疾病的肥大细胞中IgE信号的反应性 和哮喘肺除了调节肥大细胞功能的新机制外，这些蛋白质还可以 代表了哮喘和其他过敏性疾病的新药物靶点。

Project summary Allergic diseases such as asthma, atopic dermatitis and food allergies collectively affect 30-40% of adults and children in the U.S. and their prevalence is increasing. Current treatment strategies generally rely upon either neutralizing individual mediators and/or dampening the immune response. However, targeting single mediators in an inflammatory response only removes a fraction of the inflammatory “pool” of mediators and effective novel therapeutics that directly and specifically target inflammatory mast cells is an unmet need. All allergic diseases share a common feature of altered mast cell phenotype resulting in chronic hypersecretion of proinflammatory mast cell mediators such as histamine, serotonin, leukotrienes, prostaglandins, proteases and cytokines. It is likely that inherited genetic characteristics and environmental/epigenetic alterations play important roles in development of this allergic mast cell phenotype. Interestingly, human linkage analysis has identified that the gene loci 11q12-q13 are strongly linked to allergy and asthma susceptibility. The Membrane Spanning (MS)4A gene cluster encodes a family of at least 16 genes in humans that are expressed in immune cells. Current evidence suggests a link between the MS4A family and diseases associated with inflammation. The entire MS4A gene cluster lies within 11q12-q13, suggesting a potential linkage to allergy. In this application, we propose that the MS4A gene cluster plays a critical role in the development of a hyper- responsive mast cell phenotype. Currently, only two of these genes have been studied in detail and both play important roles in immune cell signaling and function. In this study, we will establish the roles of the MS4A gene cluster in human mast cell function and identify MS4A proteins as novel regulators of FcεRI trafficking and signaling that define human mast cell function and responsiveness to IgE signals in mast cells from non-diseased and asthmatic lung. In addition to novel mechanisms that regulate mast cell function, these proteins could represent new drug targets for asthma and other allergic diseases.