MEFV GENE STUDY USING TRANSGENIC MOUSE MODELS

使用转基因小鼠模型进行 MEFV 基因研究

• 批准号: 6162608
• 负责人: P P LIU
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162608
• 关键词: autoantigens; autosomal recessive trait; gene expression; gene mutation; gene targeting; genetic disorder; genetically modified animals; in situ hybridization; laboratory mouse; phenotype; protein structure function; rheumatism

Familial Mediterranean fever (FMF) is an autosomal recessive disease frequently seen in non-Ashkenazi Jews, Arabs, Armenians, and Turks. The main clinical features include periodic attacks of fever and serositis, sometimes complicated with amyloidosis. The gene mutated in this disease, MEFV, has been cloned and five different missense mutations have been identified in affected individuals, in the last exon of the gene. MEFV encodes a 3.7 kb transcript that is almost exlusively expressed in granulocytes. The encoded protein, pyrin, is a member of a family of proteins homologous to the Ro52 autoantigen. The function of pyrin is still unclear. It is likely that pyrin plays an important role in the inflammatory and immune response functions of mature granulocytes. We propose to study the function of pyrin by generating mice with either deletions or missense mutations (mimicking those in FMF patients) in the mouse MEFV gene, using standard gene targeting techniques. Phenotypes, especially changes in the maturation of granulocytes and their inflammatory and immune responses will be recorded and analyzed. The expression pattern of the gene will also be studied by RNA in situ hybridization and by generating transgenic mice with the lacZ gene under the control of MEFV promoter.

家族性地中海热是一种常染色体隐性遗传病 常见于非德系犹太人、阿拉伯人、亚美尼亚人和土耳其人。的 主要临床特征包括发热和浆膜炎的周期性发作， 有时并发淀粉样变性这种疾病的基因突变， 已经克隆了MEFV，并且已经克隆了五种不同的错义突变。 在受影响的个体中，在基因的最后一个外显子中识别。MEFV 编码一个3.7kb的转录本，几乎只在 粒细胞所编码的蛋白质，pyrin，是一个家族的成员， 与Ro52自身抗原同源的蛋白质。Pyrin的功能是 目前仍不清楚.很可能pyrin在这一过程中起着重要作用。 成熟粒细胞的炎症和免疫应答功能。我们 我建议通过产生具有以下两种基因的小鼠来研究pyrin的功能： 缺失或错义突变（模仿FMF患者中的那些）， 小鼠MEFV基因，使用标准基因靶向技术。表型， 尤其是粒细胞成熟的变化及其 将记录和分析炎症和免疫应答。的 该基因的表达模式也将通过RNA原位研究 杂交，并通过产生具有lacZ基因的转基因小鼠， MEFV启动子的调控。