BHLH proteins in human lymphopoiesis

人干细胞在轻度辐照NOD/SCID小鼠骨髓中有效定植，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，该系统可以研究人类淋巴细胞形成的许多分子方面。对小鼠的研究表明，B和T转录抑制因子Id-1及其相关分子可以在非常早期的阶段阻断这两条分化途径。而调节HLH功能的细胞外信号则定义不清。Notch在早期淋巴细胞前体的命运决定中发挥作用，可能部分通过阻断E2A基因的HLH蛋白产物来实现。我们将获得关于各种HLH家族成员、Id蛋白、Notch和Notch配体在人B细胞前体中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，在将其移植到NOD/SCID小鼠身上之前，对人类干细胞进行卡带测试。淋巴细胞存活、增殖和分化的改变将被彻底描述。由于已知E2A和相关分子具有肿瘤抑制作用，恶性肿瘤也有可能发展。这些实验将提供关于人类淋巴系统最早期阶段正常调节机制的信息。这些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.