ROLE OF HNF4ALPHA IN TERM OF LIVER REGENERATION AND HEPATOCYTE DIFFERENTIATION

这个子项目是许多研究子项目中的一个 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的研究机构。 肝脏在部分肝切除术（PHX）或药物诱导的肝损伤后具有显著的再生能力。肝脏再生的特征在于在再生结束时精确控制器官大小，导致肝脏精确地再生长到肝切除术前的大小。调控肝再生终止和器官大小控制阻止不受控制的肝生长的机制尚不清楚。本研究的目的是探讨肝细胞核因子-4a（HNF-4a，NR 2A 1）在肝再生终止中的作用。核心假设是，HNF 4a，肝细胞分化的主要调节剂，通过抑制细胞增殖和诱导肝细胞分化参与肝再生的终止。最近的研究还表明，HNF-4a除了调节肝分化外，还可以调节细胞周期抑制剂，如p21/WAF 1。将使用肝特异性HNF-4a敲除小鼠、使用吗啉代反义寡核苷酸在野生型小鼠中敲低HNF-4a以及在PHX之前通过体内基因递送过表达HNF-4a之后研究HNF-4a在PHX后肝再生终止中的作用。此外，我们将研究HNF-4a是否可以控制在肝部分切除术后肝再生终止过程中关键细胞周期调节因子的表达。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. Liver has a remarkable capacity to regenerate following partial hepatectomy (PHX) or drug-induced liver injury. Regeneration of liver is characterized by the precise control of organ size at the end of regeneration resulting in re-growth of liver precisely to the pre-hepatectomy size. The mechanisms regulating termination of liver regeneration and organ size control prohibiting uncontrolled liver growth are unclear. The goal of the proposed studies is to investigate the role of Hepatocyte Nuclear Factor-4a (HNF-4a, NR2A1) in termination of liver regeneration. The central hypothesis is that, HNF4a, a master regulator of hepatocyte differentiation is involved in termination of liver regeneration by inhibiting cell proliferation and inducing hepatocyte differentiation. Recent studies have also demonstrated that HNF-4a, in addition to regulating hepatic differentiation, can also regulate cell cycle inhibitors, such as p21/WAF1. The role of HNF-4a in termination of liver regeneration after PHX will be studied using liver specific HNF-4a knockout mice, HNF-4a knockdown in wild type mice using morpholino antisense oligos, as well as following over expression of HNF-4a by in vivo gene delivery prior to PHX. Further, we will investigate whether HNF-4a can control expression of key cell cycle regulators during termination of liver regeneration after partial hepatectomy. 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.