GENETIC AND HORMONAL REGULATION OF MURINE HEPATOCARCINOGENESIS

我们研究计划的目标是了解 专一性基因控制近交系小鼠对 肝癌的发生。这些研究将为我们提供对 多阶段关键调控通路的功能 肝癌的发生和理解危险因素作用的范例 人类的修饰基因。我们已经确定并定位了三个基因 C3H、CBA和C57BR小鼠肝脏高易感性的测定 相对于C57BL/6小鼠的肿瘤诱导作用。Hcs基因座，由C3H携带 Cba位于第1染色体上。Hcf1基因座位于第17染色体上； 位于1号染色体上的Hcf2基因座导致了这种独特的高密度 雌性C57BR小鼠对肝癌易感性的研究的目标是 本申请的前两个目标是确定 首先将这些基因定位到HIGH进行分子鉴定 通过分析携带易感病毒的同源菌株来解决 C57BL/6背景上的等位基因，然后使用该位置信息 从分子上克隆这些基因。在第三个目标中，我们试图理解 观察到的小鼠性二型性的机制基础 肝癌的发生。具体地说，我们将验证性-- 生长激素调节的依赖差异是导致 雄性小鼠对诱发肝癌的相对敏感性增加 传给雌性老鼠。第四个目标集中在菌株的遗传基础上。 一类启动事件的生物后果的变化 对于肝癌的发生，Hras1基因的突变激活。我们会 试图定位SM小鼠携带的抑制这一途径的基因，并 确定这些基因是通过组织特异性还是细胞自主性起作用 机械装置。

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.