Human FceRI signaling

（申请人的摘要）组胺和其它炎症介质， 通过交联肥大细胞的高亲和力IgE受体FceRI释放 嗜碱性粒细胞有助于支气管收缩和粘液分泌 在哮喘中发现，而肥大细胞和嗜碱性粒细胞衍生的Th 2 细胞因子与T细胞衍生的细胞因子一起有助于募集 嗜酸性粒细胞的肺和肺的维持 微环境影响携带过敏原的肺树突状细胞， 持续驱动非定型T细胞进入Th 2亚群。的 该项目的指导假设是，理解和调节 人嗜碱性粒细胞和肥大细胞的FceRI介导的信号传导途径将 产生新的策略，以减少活动性症状和免疫 过敏性哮喘的进展我们最近的工作已经将 在少数献血者（“非释放者”）中嗜碱性粒细胞FceRI信号传导至 嗜碱性粒细胞中FceRI偶联酪氨酸激酶Syk的可逆性丧失， 而不是其他血液白细胞。在续约期间，继续工作将 确定Syk缺乏的嗜碱性粒细胞是否对哮喘有保护作用，如果 从供体支气管活检获得的肺肥大细胞中不存在Syk 如果重组Syk恢复FceRI信号传导， 在非嗜碱性粒细胞中。机制研究将检验这一假设， 嗜碱性粒细胞Syk缺乏症是由于 泛素-蛋白酶体途径，可能与Syk结合接头Cbl相关 具有E3泛素激酶活性的蛋白质。基因表达差异 将通过微阵列分析发现Syk-和Syk+嗜碱性粒细胞。Genentech 科学家们为我们提供了他们的重组人源化抗IgE mAb， rhumAb-E25，一种新的治疗剂，旨在减少循环 IgE水平，但另外证实抑制嗜碱性粒细胞FceRI表达， 信号在更新期，我们将确定rhumAb-E25治疗是否 减少轻度哮喘患者肺肥大细胞中的FceRI表达和FceRI信号传导 哮喘患者机制研究将检验IgE去除 降低FceRI稳定性和FceRI-激酶偶联。这些集成 基础研究和临床研究有望提供新的 FceRI信号通路的理解，对贡献的新见解 嗜碱性粒细胞和肥大细胞对过敏性疾病的影响，以及新的治疗方法 哮喘的治疗策略

(Applicant's Abstract) Histamine and other inflammatory mediators that are released by crosslinking the high affinity IgE receptor, FceRI, of mast cells and basophils contribute to the bronchial constriction and mucus secretion found in asthma, while mast cell and basophil-derived Th2 cytokines contribute, with T cell-derived cytokines, to the recruitment of eosinophils to the lung and to the maintenance of a lung microenvironment that influences allergen-bearing lung dendritic cells to continuously drive non-committed T cells to the Th2 subset. The guiding hypothesis of this Project is that understanding and modulating the FceRI- mediated signaling pathways of human basophils and mast cells will yield new strategies to reduce the active symptoms and immunological progression of allergic asthma Our recent work has linked the failure of basophil FceRI signaling in a minority of blood donors ("non-releasers") to a reversible loss of the FceRI- coupled tyrosine kinase, Syk, in basophils but not in other blood leukocytes. In the renewal period, continuing work will establish if having Syk-deficient basophils is protective against asthma, if Syk is absent from lung mast cells obtained by bronchial biopsy from donors with non-releaser basophils and if reconstituting Syk restores FceRI signaling in non-releaser basophils. Mechanistic studies will test the hypothesis that the basophil Syk deficiency results from increased Syk degradation by the ubiquitin-proteasome pathway, possibly linked to Cbl, a Syk-binding adaptor protein with E3 ubiquitin kinase activity. Gene expression differences between Syk- and Syk+ basophils will be discovered by microarray analysis. Genentech scientists have provided us with their recombinant humanized anti-IgE mAb, rhumAb-E25, a new therapeutic agent that was designed to reduce circulating IgE levels but proved additionally to suppress basophil FceRI expression and signaling. In the renewal period, we will determine if rhumAb-E25 treatment reduces FceRI expression and FceRI signaling in the lung mast cells of mild asthmatics. Mechanistic studies will test the hypothesis that IgE removal reduces FceRI stability and FceRI-kinase coupling. These integrated fimdamental and clinical studies are expected to provide new basic understanding of FceRI signaling pathways, new insight into the contributions of basophils and mast cells to allergic disease, and new therapeutic strategies for asthma.