The role of p100 and ReIB in B lymphopoiesis

核因子-KB信号转导通路被认为参与先天和获得性免疫反应、炎症过程、细胞凋亡的调节和癌症。最近的研究表明，核因子-KB家族成员也控制着T细胞和B细胞的发育。然而，核因子-KB在早期淋巴细胞发育中是否具有重要的细胞自主功能尚不完全确定：即在前T细胞受体(Pre-TCR)或前B细胞受体(Pre-BCR)表达之前。在拟议的项目中，我们想要研究缺乏p52/NF-KB2抑制性P100前体的小鼠的早期B细胞发育。研究表明，p100可以特异性地阻断RelB，并通过最近描述的另一种途径在RelB/NF-KB的激活中发挥重要作用。我们的初步结果表明，由于Pax5表达显著减少，PWO小鼠的B细胞发育受阻于PRO-B阶段。在对plotf小鼠的B细胞发育障碍进行了更详细的描述之后，我们计划检验RelB的结构性激活增加是否与B淋巴细胞生成受损有关，以及B细胞特异性和谱系不适当的基因在野生型和P100^小鼠的B细胞前体中是否有差异表达。由于P100基因缺陷的小鼠有髓系增生，而Pax5抑制髓系特异性基因，我们还想要检测PWO、Pro-B细胞的淋巴-髓系分化潜能。最后，我们尝试通过异位表达Pax5转基因来挽救p10Gf~小鼠的B细胞发育障碍。这些研究应该有助于更好地理解核因子-KB在B细胞早期发育中的作用，特别是P100、RelB和替代途径。

The NF-KB signal transduction pathway is known to be involved in innate and adaptive immune responses, inflammatory processes, the regulation of apoptosis and cancer. Recent reports indicate that NF-KB family members also control the development of T and B cells. However, it is not fully established whether NF-KB has important cell-autonomous functions in the development of early lymphocytes: that is before the expression of the pre-T cell receptor (pre- TCR) or the pre-B cell receptor (pre-BCR). In the proposed project we would like to investigate early B cell development in mice that lack the inhibitory p100 precursor of p52/NF-KB2. p100 has been shown to specifically block RelB and to play an important role in the activation of RelB/NF-KB via the recently described alternative pathway. Our initial results indicate that B cell development in pWO mice is arrested at the pro-B stage due to dramatically reduced Pax5 expression. After a more detailed characterization of the B cell developmental block in plOtf mice we plan to examine whether increased constitutive activation of RelB is responsible for the impaired B lymphopoiesis and whether B cell-specific and lineage-inappropriate genes are differentially expressed in B cell precursors from wild-type and p100^ mice. Since p100-deficient mice have myeloid hyperplasia and Pax5 represses myeloid-specific genes we also want to examine the lympho-myeloid differentiation potential of pWO^ pro-B cells. Finally, we attempt to rescue the B cell developmental block in p10Gf~ mice by ectopic expression of a Pax5 transgene. These studies should result in a better understanding of the role of NF-KB, in particular of p100, RelB, and the alternative pathway, in early B cell development.