C-REL GENE AND IMMUNE REGULATION

本提案的总体目的是调查c-Rel原， 癌基因在抗原受体介导的增殖中的功能， B淋巴细胞凋亡。虽然细胞内信号 B细胞抗原受体的途径已被广泛研究， 导致细胞周期进展和凋亡的分子机制 大部分都是未知的。C-Rel是NF-κ B/Rel家族的成员， 应答抗原受体信号的转录因子。被 原癌基因c-Rel与淋巴肿瘤发生密切相关 在人类和鸟类中。为促进c-Rel在免疫学中的研究， 调节和肿瘤发生，我们已经产生了c-Rel敲除小鼠 使用基因靶向方法。B和T淋巴细胞均来源于 c-Rel基因敲除小鼠在增殖反应中有缺陷 由抗原受体和各种有丝分裂原诱导。在本提案中，我们 计划（1）确定细胞周期的阶段，这取决于 c-Rel活性，（2）鉴定c-Rel中的靶基因缺陷 敲除B淋巴细胞，和（3）解决c-Rel在 体液免疫应答和免疫耐受。使用c-Rel敲除 在我们实验室产生的小鼠中，我们处于理想的位置， 抗原受体介导的细胞周期的分子事件 在B淋巴细胞中的进展，以及定义在 免疫反应和耐受性。 更好地理解 调节淋巴细胞增殖和凋亡的机制提供了 开发潜在治疗程序的基本原理， 治疗或预防免疫疾病，如免疫缺陷， 自身免疫

The overall purpose of this proposal is to investigate the c-Rel proto- oncogene function in antigen-receptor-mediated proliferation and apoptosis in B lymphocytes. Although the intracellular signaling pathways of B cell antigen receptor have been examined extensively, the molecular mechanisms leading to cell cycle progression and apoptosis are largely unknown. C-Rel is a member of the NF-kappaB/Rel family of transcription factors that respond to antigen receptor signals. Being a proto-oncogene, c-Rel is strongly linked to lymphoid tumorigenesis in both human and avian. To facilitate the studies of c-Rel in immune regulation and tumorigenesis, we have generated the c-Rel knockout mice using a gene targeting approach. Both B and T lymphocytes derived from the c-Rel knockout mice are defective in proliferative responses induced by antigen receptor and various mitogens. In this proposal, we plan to (1) determine the stage of cell cycle that is dependent upon c-Rel activity, (2) identify the target gene defect(s) in the c-Rel knockout B lymphocytes, and (3) address the in vivo role of c-Rel in humoral immune responses and immune tolerance. Using the c-Rel knockout mice generated in our laboratory, we are ideally positioned to unravel the molecular events of antigen receptor-mediated cell cycle progression in B lymphocytes, as well as to define c-Rel function in immune response and tolerance. A better understanding of the mechanisms governing lymphocyte proliferation and apoptosis provides a rationale for the development of potential therapeutic procedures to cure or prevent immune disorders, such as immunodeficiencies and autoimmunity.