TARGETED DISRUPTION OF MOUSE IGE AND IGE-RECEPTOR GENES

免疫球蛋白E激活肥大细胞是骨肉瘤发病机制中的中心事件 变态反应性疾病，在宿主防御中可能很重要 寄生虫。免疫球蛋白是由粘膜B细胞产生的。在适当的时候 刺激，包括接触IL-4，转录“生殖系” Cepsilon基因的形式存在于B细胞中，紧随其后的是 导致变量和变量并列的重组事件 恒定区基因序列与完整epsilon Heavy的合成 链条。免疫球蛋白被高亲和力受体的阿尔法链结合 肥大细胞和嗜碱性粒细胞，FcepsilonRI。FcepsilonRI的交联性 结果导致它们的激活，导致过敏病理。的目标是 这个应用程序中提供的研究是生成空的小鼠 基因打靶在Cepsilon和FcepsilonRI-α基因突变中的应用 在胚胎干细胞中。这些将在几项研究中使用。 1.Switch对完整的种系Cepsilon转录本的要求 我们将研究重组问题。Cepsilon突变体将缺少外显子 Cepsilon 1-4，但有完整的Sepsilon开关和I外显子序列。这个 转录和SMU-Sepsilon同型转换的发生将是 在野生型和突变型B细胞中进行评估。 2.将使用小鼠呼吸道炎症模型来研究其作用 IgE/FcepsilonRI在诱导支气管高反应性中的作用 空降攻击后肺炎性细胞浸润 抗原。 3.IgE和FcepsilonRI在肠道发育中的作用 肥大细胞增多症、血液嗜酸性粒细胞增多症和寄生虫清除 使用小鼠线虫寄生虫尼波斯特龙进行的研究 巴西里安。 4.Ige/FcepsilonRI在眼部炎症发生中的作用 IL-4转基因小鼠和嗜酸性粒细胞的浸润 IL-4表达的肿瘤的排斥反应将被研究。

Mast cell activation by IgE is a central event in the pathogenesis of allergic disorders and may be important in host defense against parasites. IgE is produced by mucosal B cells. Upon appropriate stimulation, including exposure to IL-4, transcription of the "germline" form of the Cepsilon gene occurs in B cells and is followed by a recombination event which results in the juxtaposition of variable and constant region gene sequences with synthesis of complete epsilon heavy chain. IgE is bound by the alpha chain of the high-affinity receptor on mast cells and basophhils, FcepsilonRI. Crosslinking of FcepsilonRI results in their activation leading to allergic pathology. The goal of the research presented in this application is to generate mice with null mutations at the Cepsilon and FcepsilonRI-alpha genes by gene targeting in embryonic stem (ES) cells. These will be used in several studies. 1. The requirement for complete germline Cepsilon transcripts in switch recombination will be examined. Cepsilon mutants will lack exons Cepsilon1-4 but have intact Sepsilon switch and I exon sequences. The occurrence of transcription and Smu-Sepsilon isotype switching will be assessed in wild-type and mutant B cells. 2. Mouse models of airways inflammation will be used to examine the role of IgE/FcepsilonRI in inducing bronchial hyperreactivity as well as pulmonary inflammatory infiltrates after challenge with airborne antigens. 3. The roles of IgE and FcepsilonRI in the development of intestinal mastocytosis, blood eosinophilia and parasite clearance will be investigated using the murine nematode parasite, Nippostrongylus brasiliensis. 4. IgE/FcepsilonRI function in the generation of the ocular inflammation of IL-4 transgenic mice and in the eosinophilic infiltration and rejection of IL-4-expressing tumors will be studied.