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Musecle cell dysfunction caused by disturbed cell adhesion and signal transduction

细胞粘附和信号转导紊乱引起的肌肉细胞功能障碍

基本信息

批准号：
12470143
负责人：
SHIMIZU Teruo
金额：
$ 9.09万
依托单位：
Teikyo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2003
项目状态：
已结题

项目摘要

The dystroglycan (DG) complex, composed of two subunits αDG and βDG, interacts with the sarcoglycan complex to form the dystrophin-glycoprotein complex. αDG is a cell surface peripheral membrane protein which binds to the components of the extracellular matrix, while βDG is a type I integral membrane protein which anchors αDG to the cell membrane via the N-terminal extracellular domain. In this study, we have investigated the mechanisms by which the defects of the DG complex causes muscle cell dysfunction.(1) We have characterized the matrix metalloproteinase (MMP) activity that disrupts the DG complex by cleaving the extracellular domain of βDG and found that this MMP is activated in the skeletal and cardiac muscles of cardiomyopathic hamsters, the model animal of sarcoglycanopathy. The results raise a therapeutic potential of the 'drugs that inhibit, this MMP activity to decelerate muscle degeneration in sarcoglycanopathy.(2) In collaboration with Professor Tatsushi Toda (University of Osaka), we have developed and analyzed fukutin-deficient chimeric mice. These animals showed severe abnormalities of brain, eye and skeletal muscle, similar to FCMD. In the brain and skeletal muscle, glycosylation and laminin-binding of αDG were disturbed. These animals will be useful for further elucidation of FCMD pathogenesis.(3) We have found that glycosylation and laminin-binding of αDG are disturbed in the brain and skeletal muscle of dystrophy chicken. These animals will be useful for further elucidation of pathogenesis of α-dystroglycanopathy.

肌营养不良蛋白-糖蛋白复合体(DG)由α-DG和β-DG两个亚基组成，与肌聚糖复合体相互作用形成肌营养不良蛋白-糖蛋白复合体。αDG是一种与细胞外基质成分结合的细胞表面外膜蛋白，而βDG是一种通过N端胞外区将αDG锚定在细胞膜上的I型整合膜蛋白。在这项研究中，我们探讨了DG复合体缺陷导致肌肉细胞功能障碍的机制。(1)我们通过裂解βDG的胞外结构域来表征破坏DG复合体的基质金属蛋白酶活性，发现这种基质金属蛋白酶在肌糖病模型动物心肌病仓鼠的骨骼肌和心肌中被激活。这些结果提高了抑制这种基质金属蛋白酶活性以减缓肌糖病肌肉退化的药物的治疗潜力。(2)与大阪大学的户田达寿教授合作，我们开发并分析了Fukutin缺陷嵌合体小鼠。这些动物表现出严重的脑、眼和骨骼肌异常，类似于FCMD。在脑和骨骼肌中，αDG的糖基化和层粘连蛋白结合受到干扰。这些动物将为进一步阐明FCMD的发病机制奠定基础。(3)我们发现营养不良鸡脑和骨骼肌中αDG的糖基化和层粘连蛋白结合受到干扰。这些动物为进一步阐明α-糖营养不良症的发病机制奠定了基础。