MECHANISTIC HEPATOCARCINOGENESIS IN FISH

描述：(改编自申请人摘要)：申请人提出 一个综合的程序来研究正常和 肿瘤生长、生长控制、致癌物代谢、DNA修复和 两种FISH模型系统中的肿瘤促进作用。新的、更快的发展 用于生物检测的真核模型以识别潜在致癌物和 致癌促进剂是迫切需要研究的。一支由 实验病理学家和生物化学家将解决这一研究需求 利用四年来持续合作中最有希望的方面。 日本青竹，一种小型水族馆硬骨鱼， 在暴露于已证实的哺乳动物基因毒性后患上肝脏肿瘤 致癌物质。短暂的潜伏期，对各种 前致癌物和降低成本，同时保持大量 接触过病毒的人主张进一步发展这种体内模型。 硬骨鱼的病灶、区域和肿瘤的形态特征 模型类似于在哺乳动物模型中看到的模型。有很大一部分人 鱼肝肿瘤是肝细胞和胆管的混合瘤。 上皮细胞。这项研究表明，鱼的肝脏得到了丰富 在胆管上皮细胞中。用彩虹鲑鱼(Oncorhynchus) MyKISS)，申请人已经开发出隔离和维护 胆管上皮细胞和肝细胞在无血清培养中提供 研究与致癌物质启动和相关事件有关的独特机会 升职。申请人假设在体外和体内的分析 胆管上皮细胞和肝细胞及其相互作用 进一步加深我们对这些重要细胞在健康和 与环境相关的肿瘤疾病。三个广泛而具体的目标 将会得到解决。它们是：1)在体内提炼青竹 定量测定正常人肝癌发生的动力学模型 和肿瘤性肝生长；2)测定致癌物的效率 鲑鱼肝细胞的激活、DNA加合物的形成和DNA修复 胆管上皮细胞和青冈肝脏；3)建立生化 生长因子和肿瘤促进剂在肝细胞和胆管中的作用 上皮细胞。将进行体外分析，以快速筛选和 鉴定那些能够起到肿瘤作用的环境化合物 推动者。在青竹模型中对这些物质进行生物测试将确定它们在 活体相关性。这项分子和细胞筛查将与In 活体生物化验以验证体外研究结果。

DESCRIPTION: (Adapted from applicant's abstract): The applicant proposes an integrated program to investigate characteristics of normal and neoplastic growth, growth control, carcinogen metabolism, DNA repair and tumor promotion in two fish model systems. The development of new, faster eukaryotic models for bioassay to identify potential carcinogens and promoters of carcinogenesis is a pressing need for research. A team of experimental pathologists and biochemists will address this research need using the most promising aspects of four years of continuous cooperation. The Japanese medaka (Oryzias latipes), a small aquarium teleost species, develops tumors of liver after exposure to proven mammalian genotoxic carcinogens. Brief latency period, sensitivity to a variety of procarcinogens and decreased cost while maintaining large numbers of exposed individuals argue for further development of this in vivo model. Morphological characteristics of foci, areas and tumors in this teleost model resemble those seen in mammalian models. A large proportion of the hepatic neoplasms of fishes are mixed tumors of hepatocytes and biliary epithelial cells. This work has shown that livers of fishes are enriched in biliary epithelial cells. Using the rainbow trout (Oncorhynchus mykiss), the applicant has developed methods for isolating and maintaining biliary epithelial cells and hepatocytes in serum free culture providing a unique opportunity for studying events related to carcinogen initiation and promotion. The applicant hypothesizes that in vitro and in vivo analyses of biliary epithelial cells and hepatocytes and their interactions will further our understanding of these important cells in health and environmentally-associated neoplastic disease. Three broad specific aims will be addressed. They are: 1) refine medaka in vivo hepatocarcinogenesis model by quantitatively determining dynamics of normal and neoplastic liver growth; 2) determine the efficiency of carcinogen activation, DNA adduct formation and DNA repair in trout hepatocytes and biliary epithelial cells and in medaka liver; and 3) establish biochemical actions of growth factors and tumor promoters in hepatocytes and biliary epithelial cells. In vitro analysis will be done to rapidly screen and identify those environmental compounds capable of acting as tumor promoters. Bioassay of these in the medaka model will determine their in vivo relevance. This molecular and cellular screening will be linked to in vivo bioassay to validate in vitro findings.