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Molecular pathogenesis of congenital muscular dystrophies and development of new therapeutic measures

先天性肌营养不良症的分子发病机制及新治疗措施的开发

基本信息

批准号：
16390256
负责人：
SHIMIZU Teruo
金额：
$ 9.76万
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：
2004
资助国家：
日本
起止时间：
2004 至 2007
项目状态：
已结题

项目摘要

Dystroglycan (DG) links the extracellular matrix with cytoskeleton. Recently, mutations of the genes encoding putative glycosyltransferases were identified in several congenital muscular dystrophies and aberrant glycosylation of α-DG has been implicated in their pathogeneses (α-dystroglycanopathy). In this study, we have obtained several novel findings concerning the molecular pathogenesis of a-dystroglycanopathy.(1) We found the protease activity that degrades the extracellular domain of β-DG specifically. This activity was suppressed by the inhibitor of MMP-2 and MMP-9. Cultured cells secreted MMP-2 and MMP-9 into the culture medium. Active MMP-2 and MMP-9 enzymes degraded the β-DG. MMP-2 and MMP-9 were activated in Duchenne muscular dystrophy and sarcoglycanopathyas well as in their model animals. These results indicate that inhibitors of MMP-2 and MMP-9 may be effective for these diseases.(2) Peripheral nerve myelination was defective in the fukutin-deficient chimeric mice, a mouse … More model of Fukuyama-type congenital muscular dystrophy. The density of myelinated nerve fibers was significantly decreased and clusters of abnormally large non-myelinated axons were ensheathed by a single Schwann cell. The sugar chain moiety and laminin-binding activity of α-DG were severely reduced in the peripheral nerve of the chimeric mice. The clustering of acetylcholine receptor was defective and neuromuscular junctions are fragmented in appearance in these mice. These results demonstrate that dysmyelination of peripheral nerve should be carefully watched in congenital muscular dystrophies.(3) We found the cleavage and secretion of the N-terminal domain of α-DG (α-DG-N). Secreted α-DG-N was both N- and 0-glycosylated.α-DG-N was detectable in the human serum and cerebrospinal fluid. These observations indicate that the cleavage of α-DG-N is a widespread event and suggest that the secreted α-DG-N might be transported via systemic circulation and that the level of α-DG-N may be altered in α-dystroglycanopathies. Less

肌营养不良聚糖（DG）是连接细胞外基质和细胞骨架的重要分子。近年来，在几种先天性肌营养不良症中发现了编码糖基转移酶的基因突变，α-DG的异常糖基化与其发病机制（α-肌营养不良聚糖病）有关。在这项研究中，我们获得了一些新的发现有关的分子发病机制的α-肌营养不良聚糖病。(1)我们发现了特异性降解β-DG胞外区的蛋白酶活性。MMP-2和MMP-9的抑制剂可抑制这种活性。培养的细胞分泌MMP-2和MMP-9到培养基中。活性MMP-2和MMP-9酶降解β-DG。MMP-2和MMP-9在Duchenne型肌营养不良症和肌聚糖病及其模型动物中被激活。这些结果表明MMP-2和MMP-9的抑制剂可能对这些疾病有效。(2)在fukutin缺陷嵌合小鼠中，外周神经髓鞘形成有缺陷， ...更多信息福山型先天性肌营养不良模型。有髓神经纤维的密度显著降低，异常大的无髓轴突簇被单个雪旺细胞包裹。嵌合体小鼠外周神经中α-DG的糖链部分和层粘连蛋白结合活性严重降低。这些小鼠的乙酰胆碱受体的聚集是有缺陷的，神经肌肉接头在外观上是碎片化的。这些结果表明，周围神经髓鞘异常应密切关注先天性肌营养不良症。(3)我们发现α-DG的N端结构域（α-DG-N）存在裂解和分泌。分泌的α-DG-N是N-和O-糖基化的，人血清和脑脊液中均可检测到α-DG-N。这些观察结果表明，α-DG-N的裂解是一种普遍的事件，并表明分泌的α-DG-N可能通过体循环转运，α-肌营养不良聚糖病中α-DG-N的水平可能改变。少