Molecular genetics of fetal liver progenitor cell self-renewal, differentiation,

描述(申请人提供)：河马信号通路已经被我们的实验室和其他实验室证明是哺乳动物肝脏中的一个关键的生长和肿瘤抑制通路。此外，我们已经证明，河马信号在抑制兼性成人肝干细胞群的激活中发挥重要作用，该细胞群通常被动员以应对 对小鼠和人类的肝脏损伤。尽管河马信号在维持成人肝脏动态平衡方面很重要，但它在调节胚胎肝祖细胞发育中的作用尚未被探索。我们现在有初步数据表明，Hippo信号在肝脏的两种主要细胞类型：肝细胞和胆管上皮细胞的发育中扮演着不同的角色。在肝细胞中，Hippo信号被激活以确保这些细胞的正常功能，而在胆管上皮细胞中，Hippo信号似乎受到抑制，从而允许Hippo途径转录共激活因子Yap和Taz指导胆管上皮细胞的命运和分化。在这项提案中，我们将探索 调节肝细胞和胆管上皮细胞中的Hippo信号并确定其转录水平 受Hippo信号影响的程序，以及Hippo信号如何与染色质环境交互作用以指导肝祖细胞的发育。此外，我们在体内进行了对河马信号新调控因子的遗传筛选，并建议在肝祖细胞发育的背景下研究这些新的河马信号通路调控因子。综上所述，我们建议的研究将推进谱系特异性干细胞自我更新、增殖和分化的研究，并为河马信号通路的调控提供新的见解。

DESCRIPTION (provided by applicant): The Hippo signaling pathway has been shown by our laboratory and others to be a critical growth and tumor suppressor pathway in the mammalian liver. Furthermore, we have shown that Hippo signaling plays an important role in suppressing activation of a facultative adult liver stem cell population that is often mobilized in response to liver injury in both mice and humans. Despite its importance in maintaining adult liver homeostasis, the role of Hippo signaling in regulating embryonic liver progenitor cell development has not been explored. We now have preliminary data indicating that Hippo signaling plays distinct roles in the development of the two major cell types of the liver: hepatocytes and biliary epithelial cells. In hepatocytes, Hippo signaling is activated to ensure proper functioning of these cells, whereas in biliary epithelial cells, Hippo signaling appears to be dampened, allowing the Hippo pathway transcriptional co---activators Yap and Taz to direct biliary epithelial cell fate and differentiation. In this proposal we will explore mechanisms that regulate Hippo signaling in hepatocytes and biliary epithelial cells and define the transcriptional programs impacted by Hippo signaling and how Hippo signaling interfaces with the chromatin landscape to direct liver progenitor cell development. Furthermore, we have conducted an in vivo genetic screen for novel regulators of Hippo signaling and we propose to study these novel Hippo pathway regulators in the context of liver progenitor cell development. Taken together, our proposed studies will advance research on lineage---specific stem cell self-renewal, proliferation, and differentiation and provide novel insights into regulation of the Hippo signalin pathway.