C-REL GENE AND IMMUNE REGULATION

这项建议的总体目的是调查c-Rel原- 癌基因在抗原受体介导的增殖和转移中的作用 B淋巴细胞的细胞凋亡。尽管细胞内的信号 B细胞抗原受体的通路已经被广泛研究， 细胞周期进展和细胞凋亡的分子机制 在很大程度上是未知的。C-Rel是核因子-kappaB/Rel家族的成员 对抗原受体信号做出反应的转录因子。存在 原癌基因c-rel与淋巴样肿瘤的发生密切相关 人类和鸟类都是如此。促进c-rel在免疫中的研究 调控和肿瘤发生，我们已经产生了c-rel基因敲除小鼠 使用基因打靶的方法。B和T淋巴细胞都来自于 C-rel基因敲除小鼠的增殖反应存在缺陷。 由抗原受体和各种有丝分裂原诱导。在这项提案中，我们 计划(1)确定依赖于的细胞周期阶段 C-Rel活性，(2)确定c-Rel中的靶基因缺陷(S 敲除B淋巴细胞，以及(3)解决c-rel在体内的作用。 体液免疫反应和免疫耐受。使用c-rel基因敲除 在我们实验室中产生的小鼠，我们处于理想的位置来解开 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，以及确定c-Rel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 开发潜在的治疗程序的基本原理 治疗或预防免疫紊乱，如免疫缺陷和 自身免疫力。

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.