FUNCTIONS OF ELF-1 AND A NOVEL ETS FACTOR NERF IN B CELLS

我们的目标是了解胚胎多能细胞是如何分化的 进入免疫系统的特定细胞类型，并识别 发育缺陷导致白血病和淋巴瘤的形成。 我们的方法是分析转录调控机制 发育调控的β细胞特异性基因和一个新的ETS的分离 NERF因子，具有三种不同的人脾和人脾剪接形式 胎儿肝脏。NERF与ELF-1密切相关，ETS因子与ELF-1相关 T细胞特异性基因的表达；然而，我们的初步结果表明 ELF-1是一种主要的β细胞核因子，它与 激活Beta细胞特异性基因中的调控元件。Nerf和 ELF-1在Beta细胞发育的早期阶段高度表达， 在几个Beta细胞特异性基因中与Ets位点具有相似亲和力的结合 亲和力最高的是Beta细胞酪氨酸激酶基因Lyn&blk。 我们建议研究NERF的作用和作用机制 和ELF-1在以blk基因为基础调控Beta细胞特异性基因中的作用 一个明显的目标基因。我们的目标是评估NERF在 β细胞发育及分析其结构/功能关系 NERF和ELF-1以了解负责功能的机制 这两个因素之间的差异。因此，具体目标是： 具体目标1。确定NERF和ELF-1在 β细胞特异性blk基因表达的调控。 特定目标2.确定蛋白质-蛋白质的作用 ELF-1或NERF功能中的相互作用和磷酸化。 具体目标3.确定定向干扰的效果 NERF基因对Beta细胞发育和blk基因表达的影响。 由于ETS家族在调节各种组织中的重要性- 和分化特异性基因，总的来说，和造血，在 特别是，NERF和ELF-1预计将在Beta中发挥核心作用 细胞发育。NERF和ELF-1在脑内的功能研究 规范Beta细胞的发展将提供令人兴奋的机会 测试假设这些ETS因子的功能改变会导致 白血病。

Our goal is to understand how embryonic pluripotent cells differentiate into specific cell types of the immune system and to identify developmental defects leading to leukemia and lymphoma formation. Our approach is to analyze transcriptional control mechanisms for developmentally regulated beta cell-specific gene and isolated a novel Ets factor, NERF, with three alternative splice forms form human spleen and fetal liver. NERF is closely related to ELF-1, and Ets factor linked to T cell-specific gene expression; however, our preliminary results indicate that ELF-1 is a major Beta cell nuclear factor which interacts with the activates regulatory elements in Beta cell-specific genes. NERF and ELF-1 are highly expressed in early stages of Beta cell development and bind with similar affinity to Ets sites in several Beta cell-specific genes the highest affinity is for the Beta cell tyrosine kinase genes, lyn & blk. We propose to investigate the role and mechanism of action of NERF and ELF-1 in regulating Beta cell-specific genes using the blk gene as one apparent target gene. Our aim is to evaluate the role of NERF in Beta cell development and analyze structure/function relationships of NERF and ELF-1 to understand mechanisms responsible for functional differences between these two factors. Thus, the specific aims are to: Specific AIM number 1. Determine the role of NERF and ELF-1 in the regulation of Beta cell specific blk gene expression. Specific Aim number 2. Determine the role of protein-protein interactions and phosphorylation in the function of ELF-1 or NERF. Specific Aim number 3. Determine the effect of targeted disruption of the NERF gene on Beta cell development and blk gene expression. Due to the importance of the Ets family in regulation of various tissue- and differentiation-specific genes, in general, and hematopoiesis, in particular, NERF and ELF-1 are expected to play a central role in Beta cell development. Elucidation of the function NERF and ELF-1 in regulating Beta cell development will provide exciting opportunities to test the hypothesis that altered functions of these Ets factor result in leukemia.