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Understanding and Ameliorating Pathogenesis in FSHD

了解和改善 FSHD 的发病机制

基本信息

批准号：
MR/P023215/1
负责人：
Peter Zammit
金额：
$ 47.32万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FP023215%2F1
关键词：
Understanding Ameliorating Pathogenesis FSHD

项目摘要

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.

如果了解症状背后的原因/机制，就可以更有效地治疗疾病。对于肌营养不良症，主要缺陷是基因或DNA的变化。然而，这是知之甚少，这些缺陷如何导致进行性骨骼肌无力和肌肉萎缩症的典型浪费。面肩肱型肌营养不良症（FSHD）是由产生一种通常不存在于肌肉中的蛋白质（DUX 4）引起的。DUX 4是一种控制其他基因的“转录因子”，从而扰乱了肌肉中基因表达的精心协调模式，导致虚弱和消瘦。DUX 4控制的许多蛋白质之一称为HIF 1 alpha。这种蛋白质在细胞对低氧水平的反应中非常重要。然而，异常持续的HIF 1 α水平可导致细胞死亡。FSHD细胞在处理代谢/呼吸的副产物（称为活性氧物质（氧化应激））方面的效率也较低，这些副产物通常由称为抗氧化剂的化合物（如维生素C）处理。重要的是，最近的一项临床试验（clinicaltrials.gov编号：NCT 01596803）报道，给予维生素C作为一组抗氧化剂的一部分，改善FSHD患者的肌肉功能。该项目将有助于更好地了解这一令人鼓舞的观察背后的机制，探索操纵HIF 1aplha水平和相关信号因子的影响，以及维生素C如何发挥其改善FSHD患者肌肉功能的作用。因此，总之，我们将产生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。更好地理解FSHD的疾病机制也可能突出其他潜在的治疗干预措施。