Characteristics of splice variants of the skeletal muscle ryanodine receptor: implications for myotonic dystrophy

该项目是为了解决一些基本的分子变化，发生在骨骼肌发育过程中和强直性肌营养不良症。强直性肌营养不良是一个重要的健康问题，因为它是最常见的成人肌营养不良症，发生率约为1/7000。这些结果将提供有关调节肌肉收缩的膜相关分子机制的急需信息，并可能为强直性肌营养不良的药物设计和治疗提供基础。呼吸和运动取决于肌肉细胞内钙离子储存的释放。Ryanodine受体钙通道调节钙库的钙释放。当兰尼碱受体表达缺陷时，出生时或出生前死亡强调了兰尼碱受体的基本性质。此外，兰尼碱受体的遗传缺陷会导致心律失常、恶性高热和中央核心疾病。兰尼碱受体功能在心力衰竭和疲劳中受损。Ryanodine受体的重要作用使其成为潜在的治疗靶点，但由于我们对该蛋白质的知识有限，它们没有以这种方式使用。强直性肌营养不良是一种常染色体显性多系统疾病，其中非编码DNA的扩增导致几种不同蛋白质表达的变化。虽然强直性肌营养不良的遗传基础现在已经相当清楚，但受影响蛋白质的分子变化对肌病的贡献尚未研究。我们的研究小组最近发现，青少年形式的兰尼碱受体蛋白在患有强直性肌营养不良的成年人中高度表达。通过发现更多关于青少年亚型的特性，我们将更多地了解兰尼碱受体在肌肉发育和强直性肌营养不良中功能的基本机制，并能够设计药物来特异性修饰兰尼碱受体活性。

The project is to address some of the basic molecular changes that occur in skeletal muscle during development and in myotonic dystrophy. Myotonic dystrophy is a significant health issue since it is the most common adult muscular dystrophy, with an occurrence of ~1 in 7000. The results will provide much needed information about the membrane-associated molecular mechanisms that regulate muscle contraction and may provide a basis for drug design and treatment of myotonic dystrophy. Respiration and locomotion depend on the release of calcium ions from stores inside muscle cells. Ryanodine receptor calcium channels regulate calcium release from the stores. The essential nature of ryanodine receptors is underlined by death at or before birth when ryanodine receptor expression is defective. In addition genetic defects in the ryanodine receptor cause cardiac arrhythmias, malignant hyperthermia and central core disease. Ryanodine receptor function is compromised in heart failure and fatigue. The essential role of ryanodine receptors makes them a potential therapeutic target, but they are not used in this way because of our limited knowledge of the protein. Myotonic dystrophy is an autosomal dominant multi-system disorder, in which an expansion of non-coding DNA leads to changes in expression of several different proteins. Although the genetic basis of myotonic dystrophy is now reasonably well understood, the contribution of molecular changes in the affected proteins to the myopathy has not been investigated. Our group has recently discovered that the juvenile form of the ryanodine receptor protein is highly expressed in adults suffering from myotonic dystrophy. By discovering more about the properties of the juvenile isoform, we will understand more about the basic mechanisms of ryanodine receptor function in developing muscle and in myotonic dystrophy and be able to design drugs to specifically modify ryanodine receptor activity.