GENETIC INSTABILITY AND KNOCKOUT MICE

遗传不稳定性和基因敲除小鼠

• 批准号: 6300621
• 负责人: NELSON FAUSTO
• 金额: $ 9.51万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-07 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300621
• 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.

描述：（申请人描述）沃纳综合征（WS）是一种常染色体隐性遗传病，由编码RecQ解旋酶家族成员的基因座（WRN）突变引起。患者患有各种各样的良性和恶性肿瘤，其中间质肿瘤的负荷相对较高。WS体细胞表现出突变表型和延长的S期。申请人正在通过靶向诱变产生两种WS小鼠模型，一种是外显子2敲除，另一种是外显子26缺失，后者模拟日本人群中最常见的突变品种。在该提案中，除了基因组不稳定性的特征和确定纯合子缺陷小鼠和野生型小鼠（均为C57BL/6背景）中各种肿瘤的患病率和谱外，他们还将对杂合子携带者进行类似的实验，鉴于其相对较高的患病率，杂合子携带者具有特殊的公共卫生利益。4-硝基喹啉-1氧化物（4NQO）、喜树碱和苯并[a]芘等基因毒性药物将被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系杂交。