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: 6556017
• 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/6556017
• 关键词: amyloidosis; autosomal recessive trait; disease /disorder model; gene expression; gene mutation; gene targeting; genetic disorder; genetically modified animals; hyperthermia; in situ hybridization; laboratory mouse; pathologic process; phenotype; point mutation; protein structure function

The aim of this study is to use transgenic mice as models to understand the role of the human Familial Mediterranean Fever (FMF) gene, MEFV, in the pathogenesis of the disease. FMF is an inherited disease with periodic fever and abdominal pain. It is very frequent in the Middle East and can be fatal due to amyloidosis and renal failure if untreated. We have cloned this gene through linkage study and positional cloning, and found that patients with FMF have point mutations in this gene. The gene is expressed specifically in maturing granulocytes, one of the target tissues of the disease process for FMF. MEFV encodes for a protein of unknown function. We have generated transgenic mice with a deletion of the MEFV gene to understand the normal function of this gene. Mice with homozygous MEFV deletions grew normally and have not shown any visible defects nor suffered any specific diseases. However, detailed analysis of granulocytes indicated that the control of apoptosis, a process through which unwanted cells can be recycled, is defective in these animals. We are also generating transgenic mice with point mutations in the MEFV gene, mimicking those found in FMF patients. Such mice can be used to confirm the importance of the mutations for the induction of the disease, and to study the pathophysiology of the disease, which may lead to a better treatment of FMF patients.

本研究的目的是利用转基因小鼠作为模型，了解人类家族性地中海热(FMF)基因MEFV在疾病发病机制中的作用。FMF是一种遗传性疾病，伴有周期性发热和腹痛。它在中东非常常见，如果不治疗，可能会因淀粉样变性和肾功能衰竭而致命。我们通过连锁研究和定位克隆的方法克隆了该基因，发现FMF患者存在该基因的点突变。该基因在成熟的粒细胞中特异表达，粒细胞是FMF疾病过程的靶组织之一。MEFV编码一种功能未知的蛋白质。我们已经产生了MEFV基因缺失的转基因小鼠，以了解该基因的正常功能。MEFV纯合子缺失的小鼠生长正常，没有表现出任何明显的缺陷，也没有遭受任何特定的疾病。然而，对粒细胞的详细分析表明，在这些动物中，细胞凋亡的控制是有缺陷的，通过这个过程，不需要的细胞可以被回收。我们还在培育MEFV基因点突变的转基因小鼠，模仿在FMF患者中发现的那些。这样的小鼠可以用来确认突变对疾病诱导的重要性，并研究疾病的病理生理学，这可能会导致对FMF患者的更好治疗。