Elucidation of Molecular Mechanism of Muscle Degenaration using Developmental Biology Technique and development of therapeutics

利用发育生物学技术阐明肌肉退化的分子机制并开发治疗方法

基本信息

批准号：
10557065
负责人：
TAKEDA Shin'ichi
金额：
$ 8.45万
依托单位：
National Institute of Neuroscience, NCNP
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Laminin-2(merosin), composed of α2, β1 and γ1 chains, is a major comnponent of skeletal muscle basal lamina. Murarions of the laminin α2 chain gene cause merosin-deficient congenital muscular dystrophy(MD-CMD). To clarify the molecular pathology ofLaminin-2(merosin), composed of α2, β1 and γ1 chains, is a major comnponent of skeletal muscle basal lamina. Murarions of the laminin α2 chain gene cause merosin-deficient congenital muscular dystrophy(MD-CMD). To clarify the molecular pathology of MD-CMD, we generated lamininarufα2 chain knock out mouse(dy^<3K>), where the expression of laminin α2 chain is completely absent. The dy^<3K>revealed typical phenotype of muscular dystrophy, therefore the mouse is accepted as an ideal model of MD-CMD at date. We precisely ezamined morphological changes of the sleletal muscle of dy^<3K>/dy^<3K>mice. On postnatal day 9(P9) a few fibers showed necrotic changes, but on P10 manuy necrotic fibers were seen. In this stage, Evans Blue dye IgG influx into muscle fibers were found along necrotic changes of muscle fibers. Several fibers began to regenerate on P11, nad numerous regenerating fibers appeared on P13. In this stage, canpase-3 antivation and TUNEL-posotive myonuclei were found in manyu regeneratin fibers. Dephosphorylation of Bad, which triggers apoptotic signaling cascade, was also detected, suggesting that the absence of laminin α2 chain results in apoptosis of early regfenerating fibers through the interruption of survival signal from the extracellular matrix. Imcomplete or abortive regenarating process. The mouse also showed incomplete myelination in peripheral nervous system and maturational abnomality in the immunne system.

由α2，β1和γ1链组成的层粘连蛋白-2（梅罗蛋白）是骨骼肌基底层薄片的主要组成部分。层粘连蛋白α2链基因的杂音会导致缺乏梅罗蛋白的先天性肌肉营养不良（MD-CMD）。为了阐明由α2，β1和γ1链组成的层粘连蛋白-2（梅罗蛋白）的分子病理，是骨骼肌基底层层层的主要组成部分。层粘连蛋白α2链基因的杂音会导致缺乏梅罗蛋白的先天性肌营养不良症（MD-CMD）。为了阐明MD-CMD的分子病理，我们生成了层层链板链链，敲除小鼠（dy^<3k>），其中完全不存在层粘连蛋白α2链的表达。 Dy^<3K>揭示了肌肉营养不良的典型表型，因此，小鼠被接受为日期MD-CMD的理想模型。我们精确地对dy^<3k>/dy^<3k>小鼠的骨骼肌的形态变化进行了抑制。在产后第9天（P9）一些纤维显示坏死变化，但在P10手动坏死纤维上。在此阶段，发现Evans蓝色染料IgG对肌肉纤维的影响以及肌肉纤维的坏死变化。 P11上有几种纤维开始再生，其中许多纤维出现在P13上。在此阶段，在许多再生纤维中发现了CANPASE-3抗体和TUNEL阳性肌核。还检测到了触发凋亡信号级联反应的BAD的去磷酸化，这表明缺乏层粘连蛋白α2链的缺乏通过从细胞外基质中中断存活信号而导致早期纤维纤维。 IMCOMPLETE或流产再生过程。该小鼠在外周神经系统和免疫系统中的成熟异常中还显示出不完全的髓鞘形成。