GROWTH REGULATION OF LIVER PROGENITOR CELLS

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所在的机构。 目前，肝移植是肝衰竭患者唯一可用的治疗方法。 替代疗法，如肝细胞移植已被寻求。 迄今为止的研究集中在鉴定和分离能够肝脏再增殖的各种肝细胞群。 这些研究表明，来自妊娠中期胎鼠的肝上皮细胞亚群在移植到损伤和正常成年大鼠肝脏后能够移植、增殖和分化成功能性肝细胞。 最近，在肝损伤期间被激活的卵圆细胞已经显示在移植后分化成肝细胞和胆管细胞。 虽然这些细胞的分离和移植能力已得到很好的表征，但控制其增殖、生长和分化的机制尚未研究。 基于我们实验室先前在大鼠肝脏发育方面的工作，我们假设卵圆细胞和能够进行肝脏再增殖的胎儿细胞亚群将表现出选择性生长优势，其标志将是不依赖于促分裂原、持续的c-Myc活性和雷帕霉素抗性。我们将通过研究这些细胞类型中涉及ERK、磷脂酰肌醇3-激酶（PI 3 K）、Akt和mTOR、JNK和Wnt/b-连环蛋白的关键促有丝分裂通路的调节来解决这一假设。 我们还将研究c-Myc/Max/Mad网络的调节。 Western免疫印迹、免疫荧光、RT-PCR和染色质免疫沉淀将用于描述这些信号网络在卵圆细胞和胎肝祖细胞增殖和生长中的作用。 拟议的研究可能会导致识别促进或抑制肝祖细胞植入和扩增的因素。 此外，鉴于卵圆细胞和肝脏祖细胞在肝癌中的作用，这些研究可能会为肝癌发生机制提供深入了解

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. At present, liver transplantation is the only available treatment for patients with liver failure. Alternative therapies such as hepatocyte transplantation have been sought. Research to date has focused on the identification and isolation of various populations of hepatic cells capable of liver repopulation. These studies have shown that a subpopulation of hepatic epithelial cells derived from the mid-gestation fetal rat are capable of engrafting, proliferating, and differentiating into functional hepatocytes upon transplantation to injured and normal adult rat liver. More recently, oval cells which are activated during liver injury have been shown to differentiate into hepatocytes and cholangiocytes upon transplantation. Although the isolation and engraftment capacity of these cells has been well characterized, the mechanisms controlling their proliferation, growth, and differentiation have not been studied. Based on previous work in our laboratory on liver development in the rat, we hypothesize that oval cells and the subpopulation of fetal cells capable of liver repopulation will exhibit a selective growth advantage, the hallmarks of which will be mitogen-independence, sustained c-Myc activity, and rapamycin resistance. We will address this hypothesis by studying the regulation of key mitogenic pathways involving ERK, phosphatidylinositol 3-kinase (PI3K), Akt and mTOR, JNK and Wnt/b-catenin in these cell types. We will also study the regulation of the c-Myc/Max/Mad network. Western immunoblotting, immunofluoresence, RT-PCR, and chromatin immunoprecipitation will be used to delineate the role of these signaling networks in oval cell and fetal liver progenitor proliferation and growth. The proposed studies may lead to the identification of factors that promote or inhibit liver progenitor cell engraftment and expansion. Furthermore, given the role of oval and liver progenitor cells in hepatic cancer, these studies may provide insight into mechanimsms of hepatic carcinogenesis