ROLE OF HNF4ALPHA IN REGULATION OF HEPATOCYTE PROLIFERATION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的目的是研究肝细胞核因子-4 α（HNF-4 α，NR 2A 1）在肝细胞增殖调节中的作用。尽管HNF 4 α在调节肝分化中的作用已被充分表征，但其在调节肝细胞增殖中的作用尚不清楚。核心假设是，HNF 4 α通过细胞周期抑制剂p21/WAF 1抑制肝细胞增殖，并且HNF 4 α介导的肝细胞增殖抑制对于发育和再生期间的肝脏稳态至关重要。HNF 4 α在抑制肝细胞增殖中的作用将使用组织特异性基因靶向结合诱导型Cre方法产生的新型小鼠模型来确定。我们将利用肝细胞增殖的良好表征模型，包括部分肝切除术和肝细胞癌。此外，我们将研究细胞周期抑制剂p21/WAF 1在HNF-4 α介导的肝细胞增殖抑制中的作用，使用尖端技术，如ChIP测定和双敲除小鼠模型。这项研究的结果不仅将揭示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的干预开辟新的靶点。

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.