Molecular Basis of Human Hepatic Progenitor Cell Formation

项目摘要 在上一个融资周期，我们研究了保证基金和最佳商业模式基金 指定内胚层采用肝命运。我们发现FGF在以下方面具有关键作用： 控制WNT抑制剂NKD 1的表达。NKD 1短暂抑制WNT 活性，这是促进肝脏命运所必需的。BMP通过激活 SMAD1.该信号通路调节几种发育调节因子的表达。像 FGF、BMP诱导NKD 1。BMP还控制几种染色质调节因子的表达 结构包括TFAP 2A和ARID 5B。在目前的建议中，我们将研究以下方面的作用： TFAP2A和ARID5B在产生肝祖细胞中的作用。我们之前也展示了 GATA 6是小鼠胚胎肝脏特化所必需的。因此，我们建议 确定GATA 6控制肝脏命运的机制。我们假设 GATA 6作为先锋转录因子促进内胚层的能力， 对感应线索做出反应

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.