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

描述（由申请人提供）：我们的实验室和其他实验室已证明Hippo信号通路是哺乳动物肝脏中的关键生长和肿瘤抑制通路。 此外，我们已经表明，Hippo信号传导在抑制兼性成体肝干细胞群的激活中起着重要作用，该干细胞群通常是响应于 小鼠和人类的肝损伤。 尽管Hippo信号在维持成人肝脏稳态中的重要性，但其在调节胚胎肝祖细胞发育中的作用尚未被探索。 我们现在有初步的数据表明，Hippo信号在肝脏的两种主要细胞类型的发育中起着不同的作用：肝细胞和胆管上皮细胞。 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信号似乎被抑制，允许Hippo途径转录共激活因子雅普和Taz指导胆管上皮细胞的命运和分化。 在本提案中，我们将探讨各种机制， 调节肝细胞和胆管上皮细胞中的Hippo信号传导， 受Hippo信号传导影响的程序以及Hippo信号传导如何与染色质景观相互作用以指导肝祖细胞发育。 此外，我们已经进行了体内遗传筛选的新的海马信号调节器，我们建议在肝祖细胞发育的背景下研究这些新的海马通路调节器。 综上所述，我们提出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，并提供新的见解调节海马信号通路。

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.