MOLECULAR MECHANISMS OF CARCINOGENESIS IN FERAL FISH

野鱼致癌的分子机制

基本信息

批准号：
2153893
负责人：
Isaac I Wirgin
金额：
$ 11.84万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-08-01 至 1995-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2153893
关键词：
alternatives to animals in research animal population genetics athymic mouse carcinogenesis environment related neoplasm /cancer fish fresh water environment hepatocellular carcinoma mitochondrial DNA molecular cloning molecular oncology neoplasm /cancer epidemiology neoplasm /cancer genetics oncogenes restriction mapping southern blotting transcription factor transfection

项目摘要

Close to 100% of older Hudson River tomcod exhibit histologically defined hepatocellular carcinomas, whereas this condition is absent in tomcod from a clean waterway environment. The etiology of neoplasia in these fishes is unknown. However, the Hudson River has historically been subject to elevated levels of environmental insult with a multitude of known mammalian carcinogens. Increased knowledge of carcinogenesis in fishes has the potential to increase our understanding of the process of cancer induction in all vertebrates, and may result in the description of alternate species suitable for carcinogenesis testing. While other workers have addressed the environmental origin of carcinogenesis in feral fish populations, investigations on the genetic aspects of neoplasia in these organisms are lacking. This study will evaluate molecular genetic mechanisms in the carcinogenic process in Hudson River tomcod. Specifically, we will determine if Hudson River tomcod constitute a separate population with either a genetically programmed predisposition to neoplasia or increased sensitivity to environmental carcinogens. This will be accomplished through the use of mitochondrial DNA analysis and determination of tumor incidence in fish from each population exposed to clean or Hudson River environments. In addition, we will explore the potential activation of both known and novel fish oncogenes in Hudson River tomcod. This approach will involve a series of transfections of tomcod DNA into NIH3T3 cells and use of the nude mouse co-transfection assay. Transformed cells will be assayed for exogenous fish DNA sequences and oncogenes identified by use of Southern blot hybridization. Activated oncogenes will be characterized with respect to their mechanisms of activation and novel oncogenes will be cloned and characterized.

接近 100% 的老哈德逊河巨鳕表现出组织学特征肝细胞癌，而 Tomcod 中不存在这种情况来自清洁的水路环境。这些肿瘤的病因学鱼未知。然而，哈德逊河在历史上一直是遭受高水平的环境侵害已知的哺乳动物致癌物。增加对癌症发生的认识鱼类有潜力增加我们对这一过程的理解在所有脊椎动物中诱导癌症，并可能导致以下描述适合致癌测试的替代物种。而其他工作人员已经解决了致癌的环境根源野生鱼类种群，遗传方面的调查这些生物体中缺乏肿瘤。本研究将评估哈德逊河致癌过程的分子遗传机制汤姆科德。具体来说，我们将确定哈德逊河 tomcod 是否构成具有遗传编程倾向的单独人群对肿瘤或对环境致癌物的敏感性增加。这将通过使用线粒体DNA分析来完成确定暴露于环境的每个种群的鱼的肿瘤发生率干净或哈德逊河环境。此外，我们还将探索哈德逊已知和新型鱼类致癌基因的潜在激活河汤姆科德。该方法将涉及一系列的转染 tomcod DNA转入NIH3T3细胞并使用裸鼠共转染化验。将检测转化细胞的外源性鱼类 DNA 通过使用Southern印迹杂交鉴定序列和癌基因。活化的癌基因将根据其特征进行表征激活机制和新的癌基因将被克隆并特点。