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: 6758238
• 负责人: Margo A Brinton
• 金额: $ 19.55万
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6758238
• 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）： 小鼠的黄素发病率和死亡率的耐药性受单个常染色体主导等位基因（FLV）的控制。抗性小鼠对其他类型的病毒敏感，但迄今为止所有已测试的黄病毒诱导的疾病具有抵抗力，包括西尼罗河，登革热，日本脑炎和tick骨病毒。抗性小鼠和细胞培养物有效地通过黄病毒感染，但与易感小鼠相比产生的病毒产量更低。抗性表型是组成型表达的，不需要IFN诱导。通过在小鼠中的重组研究，将FIV基因座映射到小鼠5染色体上的区域。使用位置克隆策略将2'-5'-oligoadenylate合成酶基因OAS1B的等位基因确定为FIV（Perelygin等，PNAS 99：9322-9327，2002）。在10个小鼠菌株中观察到基因型和表型之间的相关性。易感黄病毒的小鼠菌株在基因的外显子4中具有C-TT跃迁，导致过早停止密码子和截短蛋白的表达。该应用建议生成许多OAS基因敲入和敲除小鼠菌株，这些菌株将在研究中用于解决以下问题。 （1）。 OAS1B抗性等位基因是否需要在易感小鼠中赋予黄病毒诱导疾病的耐药性？ （2）。 RNase L在抗性表型中起作用吗？ （3）。其他小鼠OAS1基因在针对黄病毒的宿主防御中发挥作用？ （4）。不同的小鼠OAS1基因在对特定病毒组的宿主防御中起独特的作用？ （5）。可以删除所有小鼠OAS1基因吗？在这项研究中产生的转基因小鼠的菌株不仅对于进一步研究OAS1B介导的对黄病毒诱导的疾病的抗性以及对新型细胞内抗氟维病毒途径的研究的研究，而且还代表了对其他病毒群体的先天免疫反应的未来研究的宝贵资源。