Molecular Basis of Human Hepatic Progenitor Cell Formation

项目摘要 在上一个资金周期中，我们研究了成纤维细胞生长因子和骨形态发生蛋白 指定内胚层采用肝脏命运。我们揭示了成纤维细胞生长因子在 控制一种称为NKD1的WNT抑制物的表达。NKD1暂时抑制WNT 活性，这是促进肝脏命运所必需的。BMP通过激活BMP调控肝脏命运 Smad1.该信号通路调节多种发育调节因子的表达。喜欢 成纤维细胞生长因子、骨形态发生蛋白诱导NKD1。BMP还控制着几种染色质调节剂的表达 结构包括TFAP2A和ARID5B。在目前的建议中，我们将研究 TFAP2A和ARID5B在肝祖细胞生成中的作用。我们之前也曾展示过 GATA6是小鼠胚胎肝脏发育所必需的。因此，我们建议 确定GATA6控制肝脏命运的机制。我们假设 GATA6作为一种先锋转录因子促进内胚层 对归纳提示做出反应。

Project Summary In the previous funding cycle, we examined the mechanism through which FGF and BMP specify the endoderm to adopt a hepatic fate. We revealed that FGF has a critical role in controlling expression of a WNT inhibitor called NKD1. NKD1 transiently suppresses WNT activity, which is needed to promote hepatic fate. BMP controls hepatic fate through activation of SMAD1. This signaling pathway regulates expression of several developmental regulators. Like FGF, BMP induces NKD1. BMP also controls expression of several regulators of chromatin structure including TFAP2A and ARID5B. In the current proposal, we will study the roles of TFAP2A and ARID5B in generating hepatic progenitor cells. We had also had previously shown that GATA6 is necessary for hepatic specification in mouse embryos. We, therefore, propose to determine the mechanism through which GATA6 controls hepatic fate. We hypothesize that GATA6 acts as a pioneer transcription factor to promote the competency of the endoderm to respond to inductive cues.