GENETIC MODIFIERS OF MURINE HEPATOCARCINOGENESIS

我们的研究计划的总体目标是确定和了解具体的作用机制， 调节近交系小鼠癌症发展风险的基因。这些研究将提供深入了解 小鼠肝癌发生的关键信号通路，以及理解作用的模型 人类癌症风险的修饰基因。我们已经确定Hcs 7基因座为主要决定因素， C3 H/HeJ（C3 H）和CBA/J小鼠相对于C57 BL/6 J（B6）对肝肿瘤诱导的高易感性 小鼠，并证明该基因位于远端染色体1。我们还发现， 敏感的C57 BR/cdJ（BR）小鼠携带的易感基因Hcf 2定位在同一区域。 本课题组与其他研究组对C3 H、BR和B6小鼠肝癌发生的比较研究 表明Hcs 7和Hcf 2基因座自主地作用于细胞以控制细胞的生长或发育。 癌前肝病变，但这些基因的分子身份仍然是未知的。我们有 将Hcs 7基因定位于1号染色体上6.4 Mbp的间隔。我们建议阐明其机制 Hcs 7通过以下途径调节肝癌风险。首先，我们将确定 通过定位克隆的Hcs 7的分子身份。我们将根据图谱对候选基因进行优先排序 亚厘摩根分辨率，相关菌株的共享SIMP单倍型分析，肝基因 表达和功能标准。然后，候选人将通过转基因使用细菌人工 染色体（BAG）克隆或基因置换。其次，我们将阐明Hcs 7的生物学基础。 通过比较Hcs 7 BAG转基因或等位基因替代菌株与对照来调节癌症风险 亲本或同类小鼠与肝癌发生相关的表型。最后，我们将确定 通过分析BAG转基因小鼠肝脏基因表达，探讨Hcs 7的分子机制 和同类小鼠，以及Hcs 7中携带生殖系或肝脏特异性无效突变的小鼠的表征。

The overall goal of our research program is to identify and understand the mechanisms of action of specific genes that modulate risk for cancer development in inbred mice. These studies will provide insights into the signaling pathways critical for hepatocarcinogenesis in mice, as well as models for understanding the action of modifier genes for cancer risk in humans. We have identified the Hcs7 locus as the major determinant of the high susceptibility of C3H/HeJ (C3H) and CBA/J mice to liver tumor induction relative to C57BL/6J (B6) mice and demonstrated that this gene is located on distal Chromosome 1. We also found that one of the susceptibility genes, Hcf2, carried by sensitive C57BR/cdJ (BR) mice mapped to the same region. Comparative studies of hepatocarcinogenesis in C3H, BR, and B6 mice by our group and others demonstrate that the Hcs7 and Hcf2 loci act cell autonomously to control the growth or development of preneoplastic hepatic lesions, but the molecular identities of these genes are still unknown. We have localized the Hcs7gene to a 6.4 Mbp interval on Chromosome 1. We propose to elucidate the mechanisms by which Hcs7 modulates liver cancer risk through the following approaches. First, we will determine the molecular identity of Hcs7 through positional cloning. We will prioritize candidate genes based on mapping to sub-centiMorgan resolution, analysis of shared SIMP haplotypes for relevant strains, hepatic gene expression, and functional criteria. Candidates will then be tested by transgenesis using Bacterial Artificial Chromosome (BAG) clones or gene replacement. Second, we will elucidate the biological basis for Hcs7 modulation of cancer risk by comparing Hcs7 BAG transgenic or allelic replacement strains to control parental or congenic mice for phenotypes related to hepatocarcinogenesis. Finally, we will determine the molecular mechanisms by which Hcs7 acts through analysis of hepatic gene expression in BAG transgenic and congenic mice, and characterization of mice carrying germ-line or liver-specific null mutations in Hcs7.