SSA Investigating the regulatory crosstalk between Ras signalling and the transcription factor Ebf1

EBF家族的DNA结合蛋白在不同的发育过程中发挥作用，它们的失活阻碍了正常的发育，这往往会导致人类癌症。EBF1是被研究最多的家族成员，是B淋巴细胞发育所必需的，其在急性淋巴细胞性白血病中的肿瘤抑制作用已被动物实验和遗传学研究证明。使用条件基因敲除等位基因，我们的团队已经证明EBF1是B细胞复制和生存所必需的。遗传证据表明，EBF1在人类肺组织中表达，但它在这个器官中的作用完全不清楚。在一组非小细胞肺癌中，表达显著减少，这些细胞将为机制研究提供自然发生的功能丧失工具。EBF1已被证明在B淋巴细胞发育过程中可以改变染色质状态或其靶基因的转录，但EBF1在肺组织中的作用从未被研究过。本项目的目的是研究EBF1作为肺发育的重要调节因子的潜力，以及EBF1和RAS之间的协同作用是否也与肺组织相关，EBF1和RAS是B细胞发育的特征。这将通过首先使用细胞方法在体外培养的原代细胞和转化细胞系中操纵这两条途径来实现，然后在一种独特的动物模型中进行研究，同时激活KRAS和灭活EBF1基因。

The EBF family of DNA-binding proteins play roles in various developmental processes, their inactivation blocks normal development, which often results in human cancer. The most-studied family member, Ebf1 is required for B lymphocyte development and its tumour suppressor role in acute lymphoid leukaemia has been proven by animal experiments and by genetic studies. Using a conditional knockout allele, our group has shown that Ebf1 is required for replication and survival of B cells. Genetic evidence suggests that Ebf1 is expressed in human lung tissue, but its role in this organ is entirely unknown. Expression significantly decreases in a set of non-small-cell lung carcinomas, and these cells would provide naturally occurring loss of function tools for mechanistic studies. Ebf1 has been shown to alter either the chromatin state or transcription of its target loci during B lymphocyte development, but the role of Ebf1 in lung tissue has never been addressed before.The aim of this project is to study the potential of Ebf1 as an important regulator of lung development and whether the synergism between the pathways governed by Ebf1 and RAS, which is a characteristic property of developing B cells, would be relevant in lung tissue as well. This will be achieved by first using a cellular approach to manipulate the two pathways in in vitro cultured primary cells and transformed cell lines, followed by studies in a unique animal model that simultaneously activates KRAS and inactivates the Ebf1 gene.