GENETIC AND HORMONAL REGULATION OF MURINE HEPATOCARCINOGENESIS

小鼠肝癌发生的遗传和激素调节

• 批准号: 6300173
• 负责人: Norman R. Drinkwater
• 金额: $ 23.98万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-11 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300173
• 关键词: cancer risk; carcinogenesis; cell growth regulation; cocarcinogen; gender difference; genetic mapping; genetic regulation; genetic strain; genetic susceptibility; hormone regulation /control mechanism; hormone related neoplasm /cancer; inbreeding; laboratory mouse; liver neoplasms; molecular cloning; molecular oncology; neoplasm /cancer genetics; somatotropin; tissue /cell culture

The goal of our research program is to understand the mechanisms by which specific gene control susceptibility of inbred mice to hepatocarcinogenesis. These studies will provide insights into the functions of critical regulatory pathways for multistage hepatocarcinogenesis and paradigms for understanding the action of risk- modifier genes in humans. We have identified and mapped three genes that determine the high susceptibilities of C3H, CBA and C57BR mice to liver tumor induction relative to C57BL/6 mice. The Hcs locus, carried by C3H and CBA is located on Chromosome 1. The Hcf1 locus, on Chromosome 17, and the Hcf2 locus, on Chromosome 1, are responsible for the uniquely high susceptibility of female C57BR mice to hepatocarcinogenesis. The goal of the first two aims of the present application is to determine the molecular identities of these genes by first mapping them to high resolution by analysis of congenic strains that carry the susceptible allele on a C57BL/6 background and then to use that positional information to molecularly clone the genes. In the third aim, we seek to understand the mechanistic basis for the sexual dimorphism observed in murine hepatocarcinogenesis. Specifically, we will test the hypothesis that sex- dependent differences in the growth hormone regulation are responsible for the increased sensitivity of male mice to liver tumor induction relative to female mice. The fourth aim focuses on the genetic basis for strain variation in the biological consequences of one class initiating event for hepatocarcinogenesis, mutational activation of the Hras1 gene. We will attempt to map genes carried by SM mice that suppress this pathway and to determine whether these genes act by tissue specific or cell autonomous mechanisms.

我们研究项目的目标是了解其中的机制