Glycosyltransferase Therapy for Myopathies

描述（由申请人提供）：肌营养不良症是美国和世界各地的严重健康问题。虽然许多形式的肌营养不良症的遗传基础是已知的，但这些疾病的治疗仍然难以捉摸。肌营养不良症最常见的遗传形式是杜氏肌营养不良症（DMD），这是一种X连锁疾病，大约每3500个男孩中就有一个患有这种疾病。我们的实验室已经确定了一种新的方法，抑制mdx小鼠（DMD模型）的营养不良过程。这涉及使用转基因或基因治疗方法过度表达称为CT GalNAc转移酶的糖基转移酶。该提案旨在表征CT GalNAc转移酶（CT）抑制肌营养不良症的机制。第一个目标将测试是否过度表达utrophin，一种营养不良保留蛋白，是抑制CT转基因mdx小鼠中的肌营养不良所必需的。第二个目的将确定CT转基因mdx肌肉中utrophin和细胞外基质蛋白的表达增加是否通过对肌营养不良蛋白聚糖（骨骼肌中与CT碳水化合物糖基化的主要蛋白质）的蛋白质亲和力的变化而发生。第三个目的是测试CT GalNAc转移酶表达的增加是否抑制两种形式的先天性肌营养不良症-dy小鼠和myd小鼠模型中的肌营养不良症的发展。第四个目标将证明CT GalNAc转移酶的过表达与肌生长抑制素信号传导之间的关系。肌生长抑制素抑制是改善mdx小鼠中肌营养不良的另一种手段，并且该目的将鉴定通过改变肌肉糖基化来调节肌生长抑制素及其抑制剂的表达的新手段。该提案的长期目标是验证CT GalNAc转移酶在DMD和其他形式的肌营养不良模型中作为治疗剂的用途，并基于这些发现开发疗法。另一个长期目标是开发糖基化和肌肉生长抑制素信号之间的新联系，这可能会更广泛地影响肌肉衰老和疾病的治疗。

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.