GROWTH REGULATION OF LIVER PROGENITOR CELLS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目前，肝移植是治疗肝功能衰竭的唯一有效方法。人们一直在寻求替代疗法，如肝细胞移植。到目前为止，研究的重点是鉴定和分离具有肝脏再繁殖能力的不同群体的肝细胞。这些研究表明，孕中期胎鼠肝上皮细胞亚群在移植到受损和正常成年大鼠肝脏后，能够移植、增殖和分化为有功能的肝细胞。最近，在肝损伤过程中被激活的卵圆细胞在移植后被证明分化为肝细胞和胆管细胞。虽然这些细胞的分离和植入能力已经被很好地描述，但控制它们的增殖、生长和分化的机制还没有被研究。根据我们实验室以前在大鼠肝脏发育方面的工作，我们假设卵圆细胞和能够肝脏再繁殖的胎儿细胞亚群将显示出选择性生长优势，其特征将是丝裂原非依赖性、持续的c-Myc活性和雷帕霉素耐药。我们将通过研究ERK、磷脂酰肌醇3-激酶(PI3K)、Akt和mTOR、JNK和Wnt/b-catenin等关键有丝分裂通路在这些细胞类型中的调节来解决这一假说。我们还将研究c-Myc/Max/Mad网络的调节。免疫印迹、免疫荧光、RT-PCR和染色质免疫沉淀将被用来描述这些信号网络在卵圆细胞和胎肝前体细胞增殖和生长中的作用。拟议的研究可能导致识别促进或抑制肝祖细胞植入和扩增的因素。此外，鉴于卵圆细胞和肝祖细胞在肝癌中的作用，这些研究可能为深入了解肝癌的发生机制提供帮助。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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