GENETIC AND HORMONAL REGULATION OF MURINE HEPATOCARCINOGENESIS

我们研究计划的目标是了解 特定基因控制近交系小鼠对 肝癌发生这些研究将提供深入了解 关键调节通路的功能， 肝癌发生和理解风险作用的范例- 人类的修饰基因我们已经确定并绘制了三个基因， 测定C3 H、CBA和C57 BR小鼠对肝脏的高亲和力 相对于C57 BL/6小鼠的肿瘤诱导。Hcs基因座，由C3 H携带 CBA位于1号染色体上。位于17号染色体上的Hcf 1基因座， 位于1号染色体上的Hcf 2基因座负责独特的高 雌性C57 BR小鼠对肝癌发生的易感性。的目标 本申请的前两个目的是确定 这些基因的分子身份，首先映射到高 通过分析携带易感基因的同源菌株来解决 等位基因在C57 BL/6背景上，然后使用该位置信息 来分子克隆基因。在第三个目标中，我们试图理解 在小鼠中观察到的两性异形的机制基础 肝癌发生具体来说，我们将测试性的假设- 生长激素调节的依赖性差异是导致 雄性小鼠对肝肿瘤诱导的敏感性增加， 对雌性老鼠来说第四个目标集中在菌株的遗传基础上 一类起始事件的生物学后果的变化 对于肝癌发生，Hras 1基因的突变激活。我们将 试图绘制SM小鼠携带的抑制这一途径的基因， 确定这些基因是通过组织特异性还是细胞自主性发挥作用 机制等

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.