HEPATIC OVAL CELLS IN CULTURE AND IN VIVO

描述(改编自调查员的摘要)：证据是 先前从新的体内严重肝损伤大鼠模型中获得 呋喃强诱导肝内胆管癌变 提示典型的增生性胆管上皮细胞 改变他们沿着胆管细胞谱系分化的承诺 从而充当化生小细胞的兼性细胞前体 肠状腺或独特的导管状肝细胞样细胞。 此外，胆管细胞来源的“肠源性”的发病率非常高。 “型”腺癌好发于呋喃的肝脏 治疗过的老鼠。为了更明确地确定典型的增生性疾病 胆管上皮细胞能够发挥兼性作用 多能干细胞在胆管癌变及某些疾病中的作用 对于严重的肝损伤类型，将针对以下具体目标 追求：(1)实现养殖人群肿瘤性转化 增殖的大鼠胆管上皮细胞 有别于增殖的大鼠肝卵圆细胞群 首次建立分化潜能的目的 这些更典型的胆管细胞在转化为 筛选体外转化治疗的致瘤表型；(2) 根据初步发现，确定(A)是否共转染 编码肝细胞受体的c-met原癌基因 生长因子/分散因子(HGF/SF)和HGF/SF生长因子基因 大鼠胆管上皮细胞的体外培养 在肿瘤发生中的细胞，以及(B)如果这些各自的过度表达 基因可能与转化植株的优先分化有关 沿着小肠谱系的胆管细胞；以及(3)使用GAP 连接基因作为分子生物标记物进一步建立时间序列 增生性胆管上皮细胞的谱系关系 大鼠肝脏反应形成的肝细胞类型和导管状肝细胞 对呋喃引起的严重肝损伤。据预计， 拟议的研究产生的结果可能会在 加深我们目前对肝脏的理解的一个重要途径 干细胞假说，以及对我们现在的贡献 对肝胆细胞起源和组织发生的认识 癌症。

DESCRIPTION (adapted from the investigator's abstract): Evidence was previously obtained from novel in vivo rat models of severe liver injury and intrahepatic cholangiocarcinogenesis induced by furan to strongly suggest that typical hyperplastic bile ductular epithelial cells can alter their commitment to differentiate along the biliary cell lineage so as to act as facultative cell progenitors of either metaplastic small intestinal-like glands or of unique ductular hepatocytic-like cells. Moreover, a very high incidence of biliary cell-derived "intestinal- type" adenocarcinomas preferentially developed in the livers of the furan treated rats. To more definitively establish if typical hyperplastic bile ductular epithelial cells are capable of acting as a facultative pluripotent stem-like cell during cholangiocarcinogenesis and in certain types of severe hepatic injury, the following specific aims will be pursued: (1) Achieve neoplastic transformation of cultured populations of rat hyperplastic bile ductular epithelial cells that are clearly distinct from proliferating rat liver oval cell populations for the purpose of establishing for the first time the differentiation potential of these more typical bile ductular cells when converted to their tumorigenic phenotype by selected in vitro transforming treatments; (2) Based on the preliminary findings, determine if (a) cotransfection of both the c-met protooncogene, which encodes the receptor for hepatocyte growth factor/scatter factor (HGF/SF), and the HGF/SF growth factor gene into cultured populations of rat hyperplastic bile ductular epithelial cells in tumorigenic, and (b) if the overexpression of these respective genes may correlate with a preferential differentiation of transformed biliary cells along the small intestinal lineage; and (3) Use gap junction genes as molecular biomarkers to further establish the temporal lineage relationship between hyperplastic bile ductular epithelial cell types and ductular hepatocytes that form in the rat liver in response to severe hepatic injury induced by furan. It is anticipated that the results generated by the proposed research are likely to contribute in a significant way to furthering our current understanding of the hepatic stem cell hypothesis, as well as to add considerably to our present knowledge of the cellular origins and histogenesis of hepatobiliary cancers.