BHLH proteins in human lymphopoiesis

人类干细胞有效地在轻度照射的NOD/SCID小鼠的骨髓中定植，并在B淋巴细胞谱系途径中活跃地产生细胞。通过逆转录病毒基因导入方法，该系统使研究人类淋巴细胞形成的许多分子方面成为可能。对小鼠的研究表明，B和T转录抑制因子ID-1和相关分子可以在非常早期的阶段阻断这两种分化途径。而调节促黄体生成素功能的细胞外信号却没有明确的定义。Notch在早期淋巴细胞前体细胞的命运决定中发挥作用，可能部分是通过阻断E2a基因的HLH蛋白产物来实现的。我们将获得关于人类B细胞前体中各种HLH家族成员、ID蛋白、Notch和Notch配体的正常基因表达模式的详细信息。然后将用NOD/SCID嵌合体模型进行实验，在移植到NOD/SCID小鼠之前将盒式磁带测试到人类干细胞中。淋巴细胞存活、增殖和分化的变化将被彻底描述。也有可能会发生恶性肿瘤，因为E2A和相关分子被认为具有肿瘤抑制因子的功能。这些实验将提供有关人类淋巴生成最早阶段的正常调节机制的信息。这一发现应该与理解免疫缺陷和自身免疫性疾病以及恶性肿瘤有关。

Human stem cells efficiently colonize the bone marrow of lightly irradiated NOD/SCID mice and active produce cells in the B lymphocyte lineage pathway. With retroviral gene introduction methods, this system makes it possible to investigate many molecular aspects of human lymphocyte formation. Studies with mice indicate that B and T transcriptional repressor Id-1 and related molecules can block both pathways of differentiation at very early stages. While extracellular cues that regulate HLH function are poorly defined. Notch plays a role in fate decisions made by early lymphocyte precursors and may do so in part by blocking HLH protein products of the E2A gene. We will obtain detailed information about the normal patterns of gene expression for various HLH family members, Id proteins, Notch and Notch ligands in human B cell precursors. Experiments will then be done with the NOD/SCID chimera model to test cassettes into human stem cells before transplantation to NOD/SCID mice. Alterations in lymphocyte survival, proliferation and differentiation will be thoroughly characterized. It is also possible that malignancies will develop since E2A and related molecules are known to function as tumor suppressors. These experiments will provide information about mechanisms for normal regulation of the very earliest stage in human lymphopoiesis. The findings should be relevant to understanding immunodeficiency and autoimmune disease as well as malignancies.