Overexpression of the cytotoxic T cell (CT) carbohydrate inhibits muscular dystrophy in the dyW mouse model of congenital muscular dystrophy 1A.
Overexpression of the cytotoxic T cell (CT) carbohydrate inhibits muscular dystrophy in the dyW mouse model of congenital muscular dystrophy 1A.
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DOI：
10.2353/ajpath.2007.060927
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发表时间：
2007-07
期刊：
影响因子：
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通讯作者：
Rui Xu;K. Chandrasekharan;J. Yoon;M. Camboni;Paul T. Martin
中科院分区：
文献类型：
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作者：
Rui Xu;K. Chandrasekharan;J. Yoon;M. Camboni;Paul T. Martin
最近的一些研究表明，转基因对Duchenne肌营养不良症的MDX小鼠模型的肌肉病理发展具有治疗作用，但没有一项研究被证明对层粘连蛋白α2缺陷型先天性肌营养不良症(MDC1A)的小鼠模型也有效。在这里，我们证明了细胞毒性T细胞(CT)GalNAc转移酶(Galgt2)的过表达在抑制MDC1A的Dy(W)小鼠模型的肌肉病理发展方面是有效的，就像我们之前在MDX动物中所显示的那样。转基因小鼠骨骼肌中Galgt2的胚胎过表达或出生后使用腺相关病毒的过表达都降低了dy(W)/dy(W)骨骼肌的肌肉病理程度。与MDX小鼠一样，Galgt2转基因在dy(W)/dy(W)肌纤维中的胚胎过表达抑制了肌肉的生长，而出生后的过表达则没有。胚胎和出生后Galgt2在dy(W)/dy(W)肌肉中的过表达都增加了agrin的表达，而另一种疾病修饰因子laminin alpha1则没有表达。Galgt2的过表达也刺激了甘油酯与CT碳水化合物的糖基化，在出生后的过表达实验中，糖脂占了CT反应物质的大部分。这些实验证明，Galgt2过表达在改变dy(W)小鼠骨骼肌的疾病进展方面是有效的，应该被认为是MDC1A的治疗靶点。
A number of recent studies have demonstrated therapeutic effects of transgenes on the development of muscle pathology in the mdx mouse model for Duchenne muscular dystrophy, but none have been shown also to be effective in mouse models for laminin alpha2-deficient congenital muscular dystrophy (MDC1A). Here, we show that overexpression of the cytotoxic T cell (CT) GalNAc transferase (Galgt2) is effective in inhibiting the development of muscle pathology in the dy(W) mouse model of MDC1A, much as we had previously shown in mdx animals. Embryonic overexpression of Galgt2 in skeletal muscles using transgenic mice or postnatal overexpression using adeno-associated virus both reduced the extent of muscle pathology in dy(W)/dy(W) skeletal muscle. As with mdx mice, embryonic overexpression of the Galgt2 transgene in dy(W)/dy(W) myofibers inhibited muscle growth, whereas postnatal overexpression did not. Both embryonic and postnatal overexpression of Galgt2 in dy(W)/dy(W) muscle increased the expression of agrin, a protein that, in recombinant form, has been shown to ameliorate disease, whereas laminin alpha1, another disease modifier, was not expressed. Galgt2 over-expression also stimulated the glycosylation of a gly-colipid with the CT carbohydrate, and glycolipids accounted for most of the CT-reactive material in postnatal overexpression experiments. These experiments demonstrate that Galgt2 overexpression is effective in altering disease progression in skeletal muscles of dy(W) mice and should be considered as a therapeutic target in MDC1A.