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: 6109027
• 负责人: PU PAUL 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/6109027
• 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 many missense mutations have been identified in affected individuals, in several exons 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. We have identified the mouse MEFV gene, constructed a gene targeting vector which was introduced into mouse embryonic stem (ES) cells to disrupt the mouse MEFV gene in exon 3. We are currently using these ES cells to generate mice with this MEFV mutation.

家族性地中海热（FMF）是一种常染色体 这种隐性疾病常见于非德系犹太人，阿拉伯人， 亚美尼亚人和土耳其人。主要临床特征包括周期性 发烧和浆膜炎发作，有时并发 淀粉样变性在这种疾病中发生突变的基因MEFV已经被 克隆和许多错义突变已被确定， 受影响的个体，在基因的几个外显子中。MEFV编码一个 3.7 kb转录物，几乎只在粒细胞中表达。 所编码的蛋白质，pyrin，是蛋白质家族的一员 与Ro52自身抗原同源。Pyrin的功能仍然是 不清楚很可能pyrin在这一过程中起着重要作用。 炎症和免疫反应功能的成熟 粒细胞我们建议通过以下方法来研究pyrin的功能： 产生缺失或错义突变的小鼠 （模拟FMF患者中的那些）在小鼠MEFV基因中， 标准的基因定位技术我们已经确认了老鼠的身份 MEFV基因，构建了基因打靶载体， 引入小鼠胚胎干细胞（ES细胞）以破坏 小鼠MEFV基因外显子3。我们目前正在使用这些胚胎干细胞 来制造携带MEFV突变的小鼠。