GENETIC INSTABILITY AND KNOCKOUT MICE

遗传不稳定性和基因敲除小鼠

• 批准号: 6570180
• 负责人: NELSON FAUSTO
• 金额: $ 24.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6570180
• 关键词: Werner's syndrome; benzopyrenes; biological models; camptothecin; cancer risk; chemical related neoplasm /cancer; gene mutation; genetically modified animals; helicase; laboratory mouse; model design /development; molecular pathology; neoplasm /cancer genetics; polymerase chain reaction; quinoline; site directed mutagenesis; tissue /cell culture

DESCRIPTION: (Applicant's Description) The Werner syndrome (WS) is an autosomal recessive disorder caused by mutations at a locus (WRN) coding for a member of the RecQ family of helicases. Patients suffer from a wide variety of benign and malignant neoplasms, with a relative high load of mesenchymal tumors. WS somatic cells exhibit mutator phenotypes and elongated S phases. The applicants are generating two mouse models of WS via targeted mutagenesis, an exon 2 knockout and an exon 26 deletion, the latter emulating the commonest variety of mutation in the Japanese population. In the proposal, in addition to the characterization of genomic instability and the determination of the prevalence and spectra of various neoplasms in homozygous deficient and wild-type mice (all on a C57BL/6 background), they will carry out comparable experiments with heterozygotic carriers, which are of special public health interest, given their relative high prevalence. Treatments with genotoxic agents, 4-nitroquinoline-1 oxide (4NQO), camptothecin, and benzo[a]pyrene, will be used as models of gene-environmental interactions with these three genotypes. In future experiments, homozygotes and heterozygotes will be crossed with other transgenic mouse lines relevant to the modulation of WRN gene action.

产品说明：Werner综合征（WS）是由编码解旋酶RecQ家族成员的基因座（WRN）处的突变引起的常染色体隐性病症。 患者患有各种各样的良性和恶性肿瘤，具有相对高的间叶肿瘤负荷。 WS体细胞表现出增变基因表型和延长的S期。申请人正在通过靶向诱变产生两种WS小鼠模型，外显子2敲除和外显子26缺失，后者模拟日本人群中最常见的突变种类。 在该提案中，除了对基因组不稳定性进行表征以及确定纯合缺陷和野生型小鼠中各种肿瘤的患病率和谱（均在C57 BL/6背景下）外，他们还将对杂合携带者进行可比较的实验，鉴于其相对较高的患病率，这些实验具有特殊的公共卫生利益。 用遗传毒性剂4-硝基喹啉-1氧化物（4 NQO）、喜树碱和苯并[a]芘治疗，将用作这三种基因型的基因-环境相互作用模型。 在未来的实验中，纯合子和杂合子将与其他与WRN基因作用调节相关的转基因小鼠品系杂交。