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

项目4：Niemann-Pick C1：一种治疗肌营养不良的新代偿基因 肌营养不良是人类最常见和最衰弱的遗传病之一。没有治愈的方法或 目前已有治疗方法可用。一种有希望的方法是操纵补偿性或“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代偿基因，它可能至少是导致 肌肉退化。尼曼-皮克1(NPC1)病的部分原因是神经元变性， 主要是由细胞内胆固醇运输的主要缺陷引起的。我们发现NPC1 在肌肉营养不良症中，基因和蛋白质的表达减少。此外，肌肉特异性转基因 NPC1的表达显著改善了MDX小鼠营养不良表型的严重程度。 在这里，我们建议进行实验，以确定导致NPC1表达减少的机制 营养不良肌肉及其NPC1表达增加减轻严重程度的分子基础 MDX小鼠的肌营养不良症。初步结果表明，小窝蛋白-3水平的变化起作用 一个重要的角色。最后，我们将测试NPC1的表达是否减缓营养不良的发展 三种肢带型肌营养不良症(LGMD2B、2C和2F)的表型。每一个LGMD都展示了 异常小窝蛋白-3介导的事件，因此是NPC1治疗的潜在候选者。这些 研究将提高我们对肌肉退化机制的理解，并可能发现新的 Duchenne和肢带型肌营养不良症的治疗靶点 相关性(请参阅说明)： 这些研究将提供有关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NPC1传递到营养不良的肌肉，疾病的进展可能会放缓，从而改善 无论是生命的质量还是寿命。这里描述的基础研究是一个必要和重要的 这是在人类临床试验中使用这种和其他代偿基因的先驱。

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.