Glycosyltransferase Therapy for Myopathies

描述(申请人提供)：肌营养不良症在美国和全世界都是一个严重的健康问题。虽然许多形式的肌营养不良的遗传基础是已知的，但这些疾病的治疗方法仍然难以捉摸。肌营养不良症最常见的遗传形式是Duchenne肌营养不良症(DMD)，这是一种X连锁疾病，大约每3500名男孩中就有一名患有这种疾病。我们的实验室已经确定了一种新的方法来抑制DMD模型MDX小鼠的营养不良过程。这涉及到一种名为CT GalNAc转移酶的糖基转移酶的过度表达，无论是使用转基因方法还是基因治疗方法。这项提议试图描述CT GalNAc转移酶(CT)抑制肌营养不良的机制。第一个目标是测试在CT转基因MDX小鼠中，是否需要utroin的过度表达来抑制肌肉营养不良。第二个目的将确定在CT转基因MDX肌肉中，是否通过改变对肌营养不良蛋白的亲和力来增加utroin和细胞外基质蛋白的表达，dystroglan是骨骼肌中与CT碳水化合物糖基化的主要蛋白质。第三个目标将在两种形式的先天性肌营养不良症小鼠和myd小鼠的模型中测试CT GalNAc转移酶的增加是否抑制肌营养不良的发展。第四个目标将证明CT GalNAc转移酶过表达与肌肉生长抑制素信号之间的关系。抑制myostatin是改善mdx小鼠肌营养不良的另一种方法，这一目标将确定一种通过改变肌肉糖基化来调节myostatin及其抑制物表达的新方法。这项建议的长期目标是验证CT GalNAc转移酶在治疗DMD和其他形式的肌营养不良症模型中的使用，并基于这些发现开发治疗方法。另一个长期目标是在糖基化和肌肉抑制素信号之间开发一种新的联系，这可能会更广泛地影响肌肉老化和疾病的治疗。

DESCRIPTION (provided by applicant): Muscular Dystrophy is a serious health problem in the United States and throughout the world. While the genetic basis underlying many forms of muscular dystrophy is known, therapies for these disorders remain elusive. The most common genetic form of muscular dystrophy is Duchenne muscular dystrophy (DMD), an X-linked disorder that afflicts roughly one in every 3500 boys. Our laboratory has identified a novel means of inhibiting the dystrophic process from developing in mdx mice, a model for DMD. This involves the overexpression of a glycosyltransferase called the CT GalNAc transferase, either using transgenic or gene therapy approaches. This proposal seeks to characterize the mechanism by which the CT GalNAc transferase (CT) inhibits muscular dystrophy. The first aim will test whether overexpression of utrophin, a dystrophy-sparing protein, is required for inhibition of muscular dystrophy in CT transgenic mdx mice. The second aim will determine if increased expression of utrophin and extracellular matrix proteins in CT transgenic mdx muscles occurs via changes in protein affinity for dystroglycan, the major protein glycosylated with the CT carbohydrate in skeletal muscle. The third aim will test whether increased expression of the CT GalNAc transferase inhibits the development of muscular dystrophy in models for two forms of congenital muscular dystrophy-dy mice and myd mice. The fourth aim will demonstrate the relationship between overexpression of the CT GalNAc transferase and myostatin signaling. Myostatin inhibition is another means of ameliorating muscular dystrophy in mdx mice, and this Aim will identify a novel means of modulating expression of myostatin and its inhibitors by altering muscle glycosylation. The long- term goal of this proposal is to validate the use of the CT GalNAc transferase as a therapeutic in models for DMD and other forms of muscular dystrophy and to develop therapies based on these findings. Another long-term goal is to develop a novel connection between glycosylation and myostatin signaling that may more broadly impact therapies for muscle aging and disease.