GENETIC INSTABILITY AND KNOCKOUT MICE

遗传不稳定性和基因敲除小鼠

• 批准号: 6447962
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-04-17 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6447962
• 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：（申请人的描述）维尔纳综合征（WS）是一种常染色体隐性遗传疾病，由编码RecQ解旋酶家族成员的基因座（WRN）突变引起。 患者患有多种良性和恶性肿瘤，其中间质肿瘤的数量相对较高。 WS 体细胞表现出突变表型和延长的 S 期。申请人正在通过定向诱变（外显子 2 敲除和外显子 26 缺失）生成两种 WS 小鼠模型，后者模拟日本人群中最常见的突变类型。 在该提案中，除了表征基因组不稳定性以及确定纯合缺陷型和野生型小鼠（全部在C57BL/6背景下）中各种肿瘤的患病率和谱外，他们还将用杂合子携带者进行类似的实验，鉴于杂合子携带者的患病率相对较高，因此具有特殊的公共卫生利益。 使用基因毒性剂、4-硝基喹啉-1氧化物（4NQO）、喜树碱和苯并[a]芘的治疗将被用作这三种基因型的基因-环境相互作用的模型。 在未来的实验中，纯合子和杂合子将与与 WRN 基因作用调节相关的其他转基因小鼠品系杂交。