ROLE OF HNF4ALPHA IN REGULATION OF HEPATOCYTE PROLIFERATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究的目的是探讨肝细胞核因子-4α(HNF-4α，NR2A1)在肝细胞增殖调控中的作用。虽然HNF4α在调节肝脏分化中的作用已有很好的描述，但其在调节肝细胞增殖中的作用尚不清楚。中心假说是，HNF4α通过细胞周期抑制因子p21/WAF1抑制肝细胞增殖，而HNF4α介导的抑制肝细胞增殖对肝脏发育和再生过程中的动态平衡至关重要。HNF4pha在抑制肝细胞增殖中的作用将通过使用组织特异性基因打靶和诱导Cre方法学产生的新的小鼠模型来确定。我们将利用肝细胞增殖的典型模型，包括肝部分切除和肝细胞癌。此外，我们将利用芯片分析和双基因敲除小鼠模型等尖端技术，研究细胞周期抑制因子p21/WAF1在HNF-4α介导的抑制肝细胞增殖中的作用。这项研究的结果不仅将阐明肝脏中关键的细胞周期和器官大小调节机制，而且还将为在肝癌中观察到的不受控制的肝脏生长期间进行干预开辟新的靶点。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of the proposed studies is to investigate the role of Hepatocyte Nuclear Factor-4alpha (HNF-4alpha, NR2A1) in regulation of hepatocyte proliferation. Whereas the role of HNF4alpha in regulation of hepatic differentiation is well characterized, its role in regulation of hepatocyte proliferation is not clear. The central hypothesis is that, HNF4alpha inhibits hepatocyte proliferation via cell cycle inhibitor p21/WAF1 and the HNF4alpha-mediated inhibition of hepatocyte proliferation is critical for liver homeostasis during development and regeneration. The role of HNF4alpha in inhibition of hepatocyte proliferation will be determined using novel mouse models generated using tissue specific gene targeting combined with inducible Cre methodology. We will utilize well-characterized models of hepatocyte proliferation including partial hepatectomy and hepatocellular carcinoma. Further, we will investigate role of cell cycle inhibitor p21/WAF1 in HNF-4alpha-mediated inhibition of hepatocyte proliferation suing cutting-edge techniques such as ChIP assays and double knockout mouse models. The results of this study will not only shed light on crucial cell cycle and organ size regulation mechanisms in the liver, but will also open novel targets for intervention during uncontrolled liver growth as observed in liver cancers.