Understanding and Ameliorating Pathogenesis in FSHD

如果了解症状背后的原因/机制，疾病可以得到更有效的治疗。对于肌营养不良症来说，主要的缺陷是基因或DNA的变化。然而，对于这些缺陷是如何导致肌肉营养不良的进行性骨骼肌无力和消瘦的，目前还知之甚少。面肩肩周性肌营养不良症(FSHD)是由一种通常不存在于肌肉中的蛋白质(DUX4)的产生引起的。DUX4是一种控制其他基因的转录因子，因此打乱了肌肉中精心协调的基因表达模式，导致虚弱和消瘦。DUX4控制的众多蛋白质之一被称为HIF1α。这种蛋白质在细胞对低氧水平做出反应的方式中非常重要。然而，持续的HIF1α水平异常会导致细胞死亡。FSHD细胞在处理代谢/呼吸副产物活性氧物种(氧化应激)方面的效率也较低，通常由称为抗氧化剂的化合物来处理，如维生素C。重要的是，最近的一项临床试验(临床试验.gov编号：NCT01596803)报告称，作为一组抗氧化剂的一部分，服用维生素C可以改善FSHD患者的肌肉功能。该项目将有助于更好地理解这一令人鼓舞的观察背后的机制，探索操纵HIF1aplha水平和相关信号因子的效果，以及维生素C如何发挥其在改善FSHD肌肉功能方面的作用。我们将生成FSHD的工具和模型，这些工具和模型将进一步揭示疾病机制，并为测试FSHD的潜在疗法提供平台。更好地了解FSHD的发病机制也可能突出其他潜在的治疗干预措施。

Diseases can be treated more effectively if the causes/mechanisms underlying the symptoms are known. For muscular dystrophy, the primary defect is changes in genes or DNA. However, it is poorly understood how such defects cause the progressive skeletal muscle weakness and wasting typical of muscular dystrophies. Facioscapulohumeral muscular dystrophy (FSHD) is caused by production of a protein (DUX4) that is not normally present in muscle. DUX4 is a 'transcription factor' that controls other genes, thus upsetting the carefully coordinated pattern of gene expression in muscle, leading to weakness and wasting. One the many proteins that DUX4 controls is called HIF1alpha. This protein is very important in the way that a cell responds to low oxygen levels. However, abnormal sustained HIF1alpha levels can lead to cell death. FSHD cells are also less efficient at dealing with by-products of metabolism/respiration called reactive oxygen species (oxidative stress), which are normally dealt with by compounds called anti-oxidants, such as Vitamin C. Importantly, a recent clinical trial (clinicaltrials.gov number: NCT01596803) reported that administration of Vitamin C, as part of a panel of anti-oxidants, improved muscle function in FSHD patients.This project will help better understand the mechanism behind this encouraging observation in exploring the effects of manipulating HIF1aplha levels and associated signalling factors and how Vitamin C exerts its effects in improving musclefunction in FSHD.Thus in summary, we will generate tools and models of FSHD that will both further reveal disease mechanisms and also provide a platform for testing potential therapies for FSHD. Better understanding the disease mechanism in FSHD may also highlight other potential therapeutic interventions.