GENETIC MODIFIERS OF MURINE HEPATOCARCINOGENESIS

小鼠肝癌发生的基因修饰因子

基本信息

批准号：
7603021
负责人：
Norman R. Drinkwater
金额：
$ 26.11万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7603021
关键词：
Alleles Apoptosis Bacterial Artificial Chromosomes Biological CBA/J Mouse Candidate Disease Gene Carcinogens Cell Proliferation Cells Chromosome Mapping Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 17 Chromosomes, Human, Pair 4 Code Comparative Study Congenic Mice Development Distal Facility Construction Funding Category Female Gene Expression Gene Transfer Techniques Gene-Modified Genes Genetic Genomics Genotype Germ Lines Goals Growth HSCH2CH(CH2CH(CH3)2)CO-Phe-Ala-NH2 Haplotypes Hepatic Hepatocarcinogenesis Human Inbred Mouse Inbred Strain Inbred Strains Mice Incidence Kinetics Laboratories Lesion Liver Liver neoplasms Localized Malignant neoplasm of liver Maps Modeling Molecular Mouse Strains Mus Partial Hepatectomy Phenotype Play Predisposition Recombinants Relative (related person)Research Resistance Resolution Risk Role Signal Pathway Signaling Pathway Gene Single Nucleotide Polymorphism Susceptibility Gene Testing Tissues Transgenic Organisms base cDNA Arrays cancer risk comparative congenic gene replacement genetic linkage analysis insight mutant null mutation positional cloning programs response

项目摘要

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.

我们研究计划的总体目标是识别和理解特定的作用机制调节近交小鼠癌症发展风险的基因。这些研究将为您提供有关信号通路对小鼠的肝癌发生至关重要，以及用于理解动作的模型用于人类癌症风险的修饰基因。我们已经确定了HCS7基因座是相对于C57BL/6J（B6），C3H/HEJ（C3H）（C3H）和CBA/J小鼠的高敏感性（CBA/J小鼠）小鼠并证明该基因位于远端染色体上。我们还发现其中一个敏感性基因HCF2，由敏感的C57BR/CDJ（BR）小鼠映射到同一区域。我们小组和其他人在C3H，BR和B6小鼠中肝癌发生的比较研究证明HCS7和HCF2基因座ACT ACT细胞自动控制以控制的生长或发展肿瘤性肝病变，但这些基因的分子身份仍然未知。我们有将HCS7Gene定位为1染色体上的6.4 MBP间隔。我们建议阐明机制 HCS7通过以下方法调节肝癌风险。首先，我们将确定 HCS7通过位置克隆的分子身份。我们将根据映射确定候选基因的优先级对于亚中心分辨率，分析相关菌株的共享SIMP单倍型，肝基因表达和功能标准。然后，将使用细菌人工来通过转基因来测试候选者染色体（袋子）克隆或基因置换。其次，我们将阐明HCS7的生物学基础通过比较HCS7袋转基因或等位基因替代菌株来调节癌症风险与肝癌发生有关的表型的父母或先天小鼠。最后，我们将确定 HCS7通过分析袋转基因中的肝基因表达来起作用的分子机制和先天小鼠，以及在HCS7中携带种系或特异性无效突变的小鼠的表征。