Oas-1 gene transgenic mice for WNV research.

用于 WNV 研究的 Oas-1 基因转基因小鼠。

• 批准号: 6876512
• 负责人: Margo A Brinton
• 金额: $ 18.41万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876512
• 关键词: Flaviviridae; West Nile virus; adenylate cyclase; biomedical resource; biotechnology; disease /disorder model; electroporation; endoribonucleases; enzyme activity; gene expression; gene mutation; genetic strain; genetic susceptibility; genetically modified animals; immune tolerance /unresponsiveness; immunity; laboratory mouse; microarray technology; model design /development; phenotype; polymerase chain reaction; pulsed field gel electrophoresis; southern blotting; virus diseases; virus replication; virus virus interaction

DESCRIPTION (provided by applicant): Resistance to flavivirus morbidity and mortality in mice is controlled by a single autosomal-dominant allele (Flv). Resistant mice are susceptible to other types of viruses but are resistant to disease induced by all flaviviruses tested to date, including West Nile, Dengue, Japanese encephalitis and tickborne encephalitis viruses. Resistant mice and cell cultures are efficiently infected by flaviviruses but produce lower yields of virus than susceptible mice. The resistant phenotype is constitutively expressed and does not require IFN induction. The FIv locus was mapped to a region on mouse chromosome 5 by recombination studies in mice. An allele of the 2'-5'-oligoadenylate synthetase gene, Oas1b, was identified as FIv using a positional cloning strategy (Perelygin et al., PNAS 99: 9322-9327, 2002). A correlation between genotype and phenotype was observed in 10 mouse strains. Mouse strains that are susceptible to flaviviruses have a C-to-T transition in exon 4 of the gene resulting in a premature stop codon and the expression of a truncated protein. This application proposes the generation of a number of Oas gene knock-in and knockout mouse strains that will be used in studies to address the following questions. (1). Is the Oas1b resistant allele all that is required to confer resistance to flavivirus-induced disease in a susceptible mouse? (2). Does RNase L play a role in the resistance phenotype? (3). Do other mouse Oas1 genes play a role in host defense against flaviviruses? (4). Do different mouse Oas1 genes play unique roles in host defense to specific groups of viruses? (5). Can all of the mouse Oas1 genes be deleted? The strains of transgenic mice generated in this study are not only essential for further studies of the mechanism of Oas1b-mediated resistance to flavivirus-induced disease as well as the study of novel intracellular anti-flaviviral pathways, but they also represent a valuable resource for future studies on innate immune responses to other groups of viruses.

描述（由申请人提供）： 小鼠对黄病毒的抵抗力发病率和死亡率是由单个常染色体显性等位基因（Flv）控制的。耐药小鼠对其他类型的病毒敏感，但对迄今为止测试的所有黄病毒引起的疾病具有抵抗力，包括西尼罗河病毒、登革热病毒、日本脑炎病毒和蜱传脑炎病毒。抗性小鼠和细胞培养物可以有效地被黄病毒感染，但产生的病毒产量比易感小鼠低。耐药表型是组成型表达，不需要 IFN 诱导。通过小鼠重组研究，FIv 基因座被定位到小鼠 5 号染色体上的一个区域。使用定位克隆策略将2'-5'-寡腺苷酸合成酶基因Oas1b的等位基因鉴定为FIv（Perelygin等人，PNAS 99：9322-9327，2002）。在 10 种小鼠品系中观察到基因型和表型之间的相关性。对黄病毒敏感的小鼠品系在基因的外显子 4 中具有 C 到 T 的转变，导致过早终止密码子和截短蛋白的表达。本申请建议产生多种 Oas 基因敲入和敲除小鼠品系，这些小鼠品系将用于解决以下问题的研究。 (1). Oas1b 抗性等位基因是赋予易感小鼠对黄病毒诱发疾病的抗性所必需的全部吗？ （2）。 RNase L 在耐药表型中发挥作用吗？ （3）。其他小鼠 Oas1 基因是否在宿主防御黄病毒方面发挥作用？ （4）。不同的小鼠 Oas1 基因在宿主对特定病毒组的防御中发挥独特的作用吗？ （5）。可以删除所有小鼠 Oas1 基因吗？本研究中产生的转基因小鼠品系不仅对于进一步研究 Oas1b 介导的黄病毒介导的疾病抵抗机制以及新的细胞内抗黄病毒途径的研究至关重要，而且它们也为研究提供了宝贵的资源。未来对其他病毒组的先天免疫反应的研究。