ANIMAL MODEL OF HUMAN HEPATOCYTE CARCINOGENESIS

几年前开发出了转基因小鼠，在其中白蛋白(AL) 利用增强子/启动子靶向表达尿激酶型 纤溶酶原激活物(UPA)对肝细胞的作用。有两个占优势的 这些小鼠的表型：首先，有一半的小鼠出现新生儿出血 转基因后代；第二，uPA对剩余后代的肝毒性 随之而来的是肝细胞克隆导致整个肝脏过度生长 删除了转基因DNA，因此不再产生uPA。Al-upa 转基因小鼠已成为研究肝脏疾病的独特模型。 再生和肿瘤，并已被证明是有效的接受者 移植的肝细胞，允许替换多达80%的肝脏 供体小鼠细胞的薄壁组织。最近，免疫受损的AL-uPA 小鼠已被用作移植大鼠肝细胞的接受者，给予 荷瘤小鼠100只：大鼠肝实质。这些结果形成了 以下提案的起点。这个项目的总体目标是 项目是开发一种不显示新生儿的鼠标模型 小鼠肝细胞可完全被人类取代的出血 肝细胞。这将允许对人类进行详细的实验检查 在活体环境中的肝癌发生，一种前所未有的方法 研究人类肝脏生物学和疾病的学科。具体地说，目标是 目的：(1)用含有以下成分的肝脏构建转基因小鼠并对其进行鉴定 人肝细胞；(2)检测基因毒素的致癌性 人源化小鼠肝脏中的化学物质；以及(3)确定 非遗传毒性啮齿动物肝癌致癌性的研究 人源化小鼠肝脏。这一分析的结果应该确定 人源化的小鼠肝脏是否代表了一个更直接和更有意义的模型 评估潜在有毒化学物质的人体风险的系统 探员们。

Several years ago were developed transgenic mice in which the albumin (AL) enhancer/promoter was used to target expression of urokinase-type plasminogen activator (uPA) to hepatocytes. There were two dominant phenotypes in these mice: first, neonatal hemorrhaging in one-half of all transgenic progeny; second, uPA-induced hepatotoxicity in remaining progeny followed by overgrowth of the entire liver by clones of hepatocytes that had deleted transgene DNA and therefore no longer produced uPA. AL-uPA transgenic mice have become a unique model for the study of hepatic regeneration and neoplasia and have proven to be effective recipients for transplanted hepatocytes, permitting replacement of up to 80: of the liver parenchyma by donor mouse cells. More recently, immunocompromised AL-uPA mice have been used as recipients for transplanted rat liver cells, giving rise to mice bearing 100: rat hepatic parenchyma. These results form the starting point for the following proposal. The overall goal of this project is to develop a mouse model that does not display neonatal hemorrhaging in which mouse hepatocytes can be completely replaced by human hepatocytes. This would permit detailed experimental examination of human hepatocarcinogenesis in an in vivo setting, an approach unprecedented in the study of human liver biology and disease. Specifically, the aims are to: (1) generate and characterize transgenic mice with livers composed of human hepatocyte; (2) determine the hepatocarcinogenicity of genotoxic chemicals in humanized mouse liver; and (3) determine the hepatocarcinogenicity of non-genotoxic rodent liver carcinogens in humanized mouse liver. The results of this analysis should establish whether humanized mouse liver represents a more direct and meaningful model system in which to assess the human risk of potentially toxic chemical agents.