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.

我们的研究计划的目的是了解 特定的基因控制近交小鼠对 肝癌发生。这些研究将为您提供有关 多阶段关键调节途径的功能 肝癌发生和范式，用于理解风险的作用 - 人类的修饰基因。我们已经确定并绘制了三个基因 确定C3H，CBA和C57BR小鼠对肝脏的高敏感性 相对于C57BL/6小鼠肿瘤诱导。由C3H携带的HCS基因座 CBA位于1号染色体上。HCF1基因座，染色体17，和 HCF2基因座（在1染色体上）负责独特的高 雌性C57BR小鼠对肝癌发生的敏感性。目标 本应用程序的前两个目标是确定 这些基因的分子身份首先将它们映射到高 通过分析具有易感性的先天性菌株的分析 等位基因在C57BL/6背景上，然后使用该位置信息 分子克隆基因。在第三个目标中，我们试图了解 在鼠中观察到的性二态性的机理基础 肝癌发生。具体来说，我们将检验性别的假设 生长激素调节的依赖差异是为了 雄性小鼠对肝肿瘤相对的敏感性提高 给雌鼠。第四目的重点是应变的遗传基础 一个班级启动事件的生物学后果的变化 对于肝癌发生，HRAS1基因的突变激活。我们将 尝试绘制抑制此途径并将其携带的基因 确定这些基因是通过组织特异性还是细胞自主作用的 机制。