ETS FACTOR NERF AND B CELL FUNCTION

描述(申请人的描述)：免疫系统的正常功能 需要将多能干细胞分化为成熟的淋巴样细胞 细胞。这一过程中的异常可能会导致 白血病和淋巴瘤。细胞的分化和增殖 免疫系统经常对外界刺激作出反应，如 抗原或生长物质。这种反应要求受体上的 这些细胞的表面识别刺激并启动一系列 信号转导事件。这些信号对两者都是必要的 B和T细胞的发育决定和免疫应答的启动 淋巴细胞。一种分析免疫系统调节的方法 目的是分离调节B细胞特异性基因的转录因子。 特别是，调查人员最近发现了一名新的 人脾和胎儿Ets转录因子/癌基因家族NERF 肝脏，它有一个与ETS高度同源的DNA结合域 因子ELF-1。ELF-1参与T细胞的调节 细胞特异性基因表达。初步数据表明，NERF 和ELF-1在B细胞中高表达，并与其相互作用 一整套B细胞特异性基因的调控元件，包括blk， Lyn、tdt、mb-1、b29和IgH pi位点。这些基因中有许多是 B细胞发育过程中的差异调节。此外，扰乱 一些转录因子的功能，这些转录因子调节 这些基因的表达，如BSAP和EBF，导致显著的 B细胞分化和功能异常。NERF和ELF-1出现 与Lyn和LYN的启动子区域具有最高的结合亲和力 BLK酪氨酸激酶基因。正常信号需要LYN和BLK 活化抗原/受体复合体在B淋巴细胞上的转导。 拟议研究的假设是，因为NERF和ELF-1结合 具有高度亲和力的监管区域中的多个发起人 B细胞特异性基因，它们对B细胞功能和 差异化。它们可能有相反的作用，一个上调基因 一种是表达，另一种是降低表达。他们可能是多余的，而且有 相似的效应；或者在某些细胞中，一种可能比另一种更活跃 类型或处于特定的发展阶段。以进一步阐明其作用 ELF-1和NERF在B细胞发育和功能中的作用 是为了确定它们在B细胞发育的不同阶段的表达， 证明它们作为转录因子在调节 B细胞特异性基因，并确定对免疫系统功能的影响 以及当这些基因被破坏时的发育。

DESCRIPTION (Applicant's Description): Normal function of the immune system requires the differentiation of pluripotent stem cells into mature lymphoid cells. Abnormalities in this process can lead to the development of leukemias and lymphomas. The differentiation and proliferation of cells of the immune system often occur in response to external stimuli, such as antigens or growth substances. This response requires that the receptors on the surface of these cells recognize the stimulus and initiate a series of signal transduction events. These signals are necessary for both developmental decisions and initiation of immune responses by B and T lymphocytes. One approach for analyzing the regulation of the immune system is to isolate transcription factors which regulate B cell specific genes. In particular, the investigators recently identified a novel member of the Ets transcription factor/oncogene family, NERF, from human spleen and fetal liver, which has a DNA binding domain which is highly homologous to the Ets factor ELF-1. ELF-1 has been implicated in the regulation of T cell-specific gene expression. The preliminary data demonstrate that NERF and ELF-1 are highly expressed in B cells and interact with the same regulatory elements of a whole set of B cell-specific genes including blk, lyn, TdT, mb-1, B29 and the Igh pi site. Many of these genes are differentially regulated during B cell development. Furthermore, disruption of the function of some of the transcription factors which regulate the expression of these genes such as BSAP and EBF results in marked abnormalities in B cell differentiation and function. NERF and ELF-1 appear to have the highest binding affinity for the promoter regions of the lyn and blk tyrosine kinase genes. Both lyn and blk are required for normal signal transduction of the activated antigen/receptor complex on B lymphocytes. The hypothesis for the proposed studies is that, because NERF and ELF-1 bind with high affinity to the regulatory regions in the promoters of a number of B cell specific genes, they are critical for B cell function and differentiation. They may have opposing effects, one upregulating gene expression and the other downregulating it. They may be redundant and have similar effects; or one may be more active than the other in certain cell types or at certain development stages. To further elucidate the role of ELF-1 and NERF in B cell development and function the goals of this project are to determine their expression at different stages of B cell development, demonstrate their ability to function as transcription factors in regulating B cell specific genes, and determine the effect on immune system function and development when these genes are disrupted.