NIEMANN-PICK C1: A NEW COMPENSATORY GENE FOR MUSCULAR DYSTROPHIES

项目4：尼曼-皮克C1：肌肉萎缩症的新补偿基因 肌营养不良症是最普遍和使人衰弱的人类遗传疾病之一。没有治愈方法， 目前已有治疗方法。一个有希望的方法是操纵补偿或“助推器” 减缓肌肉退化进程、提高寿命和生活质量的基因。我们 已经发现了一种新的补偿基因，它可能至少是导致癌症的部分机制的基础。 肌肉退化尼曼-皮克C1（NPC 1）病部分由神经元变性引起， 主要由细胞内胆固醇运输的主要缺陷引起。我们发现NPC 1 基因和蛋白质表达在肌营养不良症中减少。此外，肌肉特异性转基因 NPC 1的表达显著改善了mdx小鼠中营养不良表型的严重性。 在这里，我们提出了实验来确定导致NPC 1表达减少的机制， 营养不良的肌肉和NPC 1表达增加改善严重性的分子基础 mdx小鼠的肌肉萎缩症。初步结果表明，小窝蛋白-3水平的变化发挥了 一个重要的角色最后，我们将测试NPC 1的表达是否减缓了营养不良的发展。 在三种肢带型肌营养不良症（LGMD 2B、2C和2F）中的表型。这些LGMD中的每一个都表现出 异常小窝蛋白-3介导的事件，因此是NPC 1治疗的潜在候选者。这些 这些研究将提高我们对肌肉退化机制的理解， 治疗杜氏肌营养不良和肢带肌营养不良的治疗靶点。 相关性（参见说明）： 这些研究将提供关于胆固醇和小窝蛋白在肌营养不良症中的作用的新信息。 通过将NPC 1递送至营养不良的肌肉，可以减缓疾病的进展，从而改善疾病的预后。 生命的质量和长度。这里所描述的基础研究是必要的和重要的 这是在人类临床试验中使用这种和其他补偿基因的先驱。

PROJECT 4: NIEMANN-PICK C1: A NEW COMPENSATORY GENE FOR MUSCULAR DYSTROPHIES Muscular dystrophies are among the most prevalent and debilitating human genetic diseases. No cures or treatments are currently available. One promising approach is manipulation of compensatory or "booster" genes that slow the progression of muscle degeneration and improve both lifespan and quality of life. We have discovered a new compensatory gene that may underlie at least a part of the mechanism that causes muscle degeneration. Niemann-Pick C1 (NPC1) disease results, in part, from neuronal degeneration, primarily caused by a major defect in intracellular cholesterol trafficking. We have discovered that NPC1 gene and protein expression is reduced in a muscular dystrophy. Furthermore, muscle-specific transgenic expression of NPC1 significantly ameliorates the severity of the dystrophic phenotype in the mdx mouse. Here, we propose experiments to determine the mechanism that leads to reduction of NPC1 expression in dystrophic muscle and the molecular basis by which increased expression of NPC1 ameliorates the severity of muscular dystrophy in the mdx mouse. Preliminary results suggest that changes in caveolin-3 levels play an important role. Finally, we will test whether NPC1 expression slows the development of the dystrophic phenotype in three limb girdle muscular dystrophies (LGMD2B, 2C and 2F). Each of these LGMDs exhibit abnormal caveolin-3 mediated events and are therefore potential candidates for NPC1 treatment. These studies will improve our understanding of the mechanisms of muscle degeneration and may identify novel therapeutic targets for treatment of Duchenne and Limb Girdle Muscular Dystrophies. RELEVANCE (See instructions): These studies will provide new information about the role of cholesterol and caveolins in muscular dystrophy. By delivering NPC1 to dystrophic muscle, the progression of the disease may be slowed, thereby improving both the quality and length of life. The basic research described here is a necessary and important precursor to the use of this and other compensatory genes in human clinical trials.