TARGETED DISRUPTION OF MOUSE IGE AND IGE-RECEPTOR GENES

IgE激活肥大细胞是肥大细胞发病机制中的中心事件， 过敏性疾病，可能是重要的宿主防御， 寄生虫IgE由粘膜B细胞产生。采取适当 刺激，包括暴露于IL-4，“生殖系”的转录 一种形式的CCR 4基因发生在B细胞中，随后是一种 重组事件，其导致可变和 合成完全重链的恒定区基因序列 链IgE与高亲和力受体的α链结合， 肥大细胞和嗜碱性粒细胞，FcepsilonRI。FcepsilonRI的交联 导致它们的活化，导致过敏性病理。的目标 在本申请中提出研究是产生具有无效的小鼠 通过基因靶向，在CCR 4和FcepsilonRI-α基因上进行突变 胚胎干细胞（ES）这些将用于几项研究。 1.在开关中对完整生殖系CCR 4转录物的要求 将检查重组。突变体会缺少外显子 Cepsilon 1 -4，但具有完整的Separate开关和I外显子序列。的 转录和Smu-Separate同种型转换的发生将是 在野生型和突变型B细胞中评估。 2.小鼠气道炎症模型将被用于研究 IgE/FcepsilonRI诱导支气管高反应性以及 气传肺内炎性浸润 抗原 3. IgE和FcepsilonRI在肠上皮细胞发育中的作用 肥大细胞增多症、血嗜酸性粒细胞增多症和寄生虫清除将 使用鼠线虫寄生虫，日本圆线虫， 巴西的。 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浸润， 将研究表达IL-4的肿瘤的排斥。

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.