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如何分化 免疫系统的特定细胞类型， 导致白血病和淋巴瘤形成的发育缺陷。 我们的方法是分析转录控制机制， 发育调节β细胞特异性基因，并分离出一种新的Ets 从人脾中提取具有三种选择性剪接形式的NERF因子， 胎肝 NERF与ELF-1密切相关，Ets因子与 T细胞特异性基因表达;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， 激活β细胞特异性基因中的调节元件。 NERF和 ELF-1在β细胞发育的早期高度表达， 与几个β细胞特异性基因中的Ets位点以相似的亲和力结合 亲和力最高的是β细胞酪氨酸激酶基因林恩和blk。 我们建议研究NERF的作用和作用机制 和ELF-1在使用blk基因调节β细胞特异性基因中作为 一个明显的靶基因。 我们的目的是评估NERF在以下方面的作用： β细胞发育和分析结构/功能关系 NERF和ELF-1了解负责功能性 这两个因素之间的差异。 因此，具体目标是： 特定AIM编号1。 确定NERF和ELF-1在 β细胞特异性blk基因表达的调节。 具体目标2. 确定蛋白质-蛋白质的作用 在ELF-1或NERF的功能中的相互作用和磷酸化。 具体目标3. 确定有针对性地破坏 NERF基因对β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，以及造血， 特别是，NERF和ELF-1预计将在Beta测试中发挥核心作用 细胞发育 说明NERF和ELF-1在细胞中的功能 调节β细胞的发育将为我们提供令人兴奋的机会， 测试这些Ets因子的功能改变导致 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.