权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Research for the pathogenesis of oculopharyngeal muscular dystrophya -establish an animal model

眼咽型肌营养不良症发病机制研究——动物模型的建立

基本信息

批准号：
13670657
负责人：
UYAMA Eiichiro
金额：
$ 2.5万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized clinically by progressive ptosis, dysphagia, and limb weakness, and by unique intranuclear inclusions in the skeletal muscle fibers. The disease is caused by the expansion of a 10-alanine stretch to 12-17 alanine residues in the poly(A)-binding protein, nuclear 1 (PABPN1 ; PABP2). While PABPN1 is a major component of the inclusions in OPMD, the exact cause of the disease is unknown. To elucidate the molecular mechanism and to construct a useful model for therapeutic trials, we have generated transgenic mice expressing the hPABPN1. Transgenic mice lines expressing a normal hPABPN1 with 10-alanine stretch did not reveal myopathic changes, whereas lines expressing high-levels of expanded hPABPN1 with a 13-alanine stretch showed an apparent myopathy phenotype, especially in old age. Pathological studies in the latter mice disclosed intranuclear inclusions consisting of aggregated mutant hPABPN1 product. Furthermore, some TUNEL positive nuclei were shown around degenerating fibers and a cluster of it in the lesion in necrotic muscle fibers. Interestingly, the degree of myopathic changes was more prominent in the eyelid and pharyngeal muscles. Further, muscle weakness in the limbs was apparent as shown by the fatigability test. Nuclear inclusions seemed to develop gradually with aging, at least after 1 week of age, in model mouse muscles. We established the first transgenic mouse model of OPMD by expressing mutated PABPN1, and our model mice appear to have more dramatic alternations in myofiber viability.

常染色体显性遗传性眼咽肌营养不良(OPMD)是一种以进行性上睑下垂、吞咽困难和肢体无力为特征的晚发型疾病，骨骼肌纤维中有独特的核内包涵体。这种疾病是由聚(A)结合蛋白核1(PABPN1；PABP2)中的10-丙氨酸延伸到12-17个丙氨酸残基引起的。虽然PABPN1是OPMD内含物的主要成分，但疾病的确切原因尚不清楚。为了阐明分子机制并为治疗试验构建有用的模型，我们产生了表达hPABPN1的转基因小鼠。表达正常hPABPN1和10-丙氨酸拉伸的转基因小鼠没有表现出肌病变化，而表达高水平hPABPN1和13-丙氨酸拉伸的转基因小鼠则表现出明显的肌病表型，特别是在老年。后一组小鼠的病理研究显示，核内包涵体由聚集性突变的hPABPN1产物组成。此外，在坏死肌纤维周围可见一些TUNEL阳性核，坏死肌纤维内可见大量TUNEL阳性核。有趣的是，眼睑和咽部肌肉的肌病变化程度更为突出。此外，疲劳性测试显示四肢肌肉无力明显。核包涵体似乎随着年龄的增长而逐渐发展，至少在一周后，在模型小鼠的肌肉中。我们通过表达突变的PABPN1建立了第一个OPMD转基因小鼠模型，我们的模型小鼠在肌纤维活性方面似乎有更戏剧性的变化。