Transcription profiling of mouse mdx animals expressing high levels of utrophin therapeutic implications for DMD

Duchenne Muscular Dystrophy (DMD) is a fatal muscle wasting disorder caused by dystrophin deficiency. Previous work suggested that increased expression of the dystrophin-related protein utrophin in the mdx mouse model of DMD can prevent dystrophic pathophysiology. Physiological tests showed that the transgenic mouse muscle functioned in a way similar to normal muscle. More recently, it has become possible to analyse disease pathways using microarrays, a sensitive method to evaluate the efficacy of a therapeutic approach. We thus examined the gene expression profile of mdx mouse muscle compared to normal mouse muscle and compared the data with that obtained from the transgenic line expressing utrophin. The data confirm that the expression of utrophin in the mdx mouse muscle results in a gene expression profile virtually identical to that seen for the normal mouse. This study confirms that a strategy to up-regulate utrophin is likely to be effective in preventing the disease. Experiment Overall Design: Here we have addressed important question of changes in the global gene expression profile of mdx mouse muscle compared to normal mouse muscle and compared the data with that obtained from the transgenic line (fiona) expressing high level of utrophin on mdx background.杜氏肌营养不良症（Duchenne Muscular Dystrophy, DMD）是一类由抗肌萎缩蛋白（dystrophin）缺失所导致的致死性肌肉消耗性疾病。既往研究表明，在DMD的mdx小鼠模型中，抗肌萎缩蛋白相关蛋白（utrophin）的表达上调可阻断肌营养不良相关的病理生理进程。生理功能实验结果显示，该转基因小鼠的肌肉功能与正常小鼠肌肉高度相似。近年来，利用基因芯片（microarrays）这一可灵敏评估治疗方案疗效的技术分析疾病通路已成为可行手段。因此，本研究对比分析了mdx小鼠与正常小鼠的肌肉基因表达谱，并将所得数据与在mdx遗传背景下高表达utrophin的转基因品系（fiona）的检测数据进行了比对。实验结果证实，在mdx小鼠肌肉中上调utrophin的表达，可使其基因表达谱与正常小鼠近乎完全一致。本研究进一步验证了通过上调utrophin表达来预防该病的治疗策略具备可行性。实验整体设计：本研究旨在解答关键科学问题，即对比mdx小鼠与正常小鼠的肌肉全局基因表达谱变化，并将所得数据与在mdx遗传背景下高表达utrophin的转基因品系（fiona）所获数据进行比对。