Understanding and Ameliorating perturbed signalling and 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，导致缺陷的是基因或DNA的变化，而这些变化反过来又会导致蛋白质的变化。然而，人们普遍对这种缺陷如何导致进行性骨骼肌无力和消瘦的典型肌营养不良症知之甚少。人体中的每个细胞都含有相同的脱氧核糖核酸，这些脱氧核糖核酸被分成几个基因，每个基因都携带着制造蛋白质的指令(S)：建造、维护和操作身体的分子。在特定的细胞类型中表达(活跃)的基因的选择，例如在肌肉纤维中，决定了产生哪些蛋白质。这赋予了细胞特殊的特性和功能。例如，肌肉基因在皮肤细胞中不表达，皮肤基因也不在肌肉细胞中表达。面肩肩周肌营养不良症(FSHD)是由DNA特定区域的变化导致一种名为DUX4的蛋白质产生引起的，这种蛋白质通常不存在于肌肉中。DUX4是一种“转录因子”，这意味着它可以通过结合其他基因的调节区来控制它们的表达，因此可以改变细胞制造的蛋白质的类型。因此，使骨骼肌有效运作的基因表达和蛋白质生产的精心协调模式，被DUX4的存在扰乱了。这最终导致肌肉虚弱和消瘦。我们研究了人类肌肉形成过程中FSHD细胞中基因表达的变化，并使用数学工具来了解哪些信号传递过程受到干扰。我们发现，控制线粒体生成和与线粒体功能相关的过程的途径，如处理代谢/呼吸的副产物，称为活性氧物种(氧化应激)，受到抑制。众所周知，FSHD细胞对氧化应激更敏感，最近的一项临床试验(Clinicaltrials.gov编号：NCT01596803)报告说，服用抗氧化剂可以改善FSHD患者的肌肉功能。我们发现，控制健康人体肌肉细胞中线粒体生成的抑制途径使它们看起来像FSHD肌肉纤维。相反，加强这些控制FSHD肌肉细胞线粒体生成的途径的作用，使它们更像健康的人类肌肉细胞。本项目将研究控制线粒体生成的这一途径的调节在FSHD中是如何受到干扰的，并测试潜在的治疗策略来改善其功能。因此，总而言之，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的潜在疗法提供一个平台，以支持可能的临床试验。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 causative defect is changes in genes or DNA that in turn, produce changes to proteins. However, it is generally poorly understood how such defects result in the progressive skeletal muscle weakness and wasting typical of muscular dystrophies. Every cell in the body contains the same DNA, which is divided into genes, each of which carries the instructions to make a protein(s): the molecules that build, maintain and operate the body. The selection of genes that are expressed (active) in a particular cell type, such as in a muscle fibre, dictate which proteins are made. This gives the cell its special characteristics and functions. For example, muscle genes are not expressed in skin cells, and skin genes are not expressed in muscle cells.Facioscapulohumeral muscular dystrophy (FSHD) is caused by a change in a particular region of DNA that leads to production of a protein called DUX4, that is not normally present in muscle. DUX4 is a 'transcription factor' meaning that it can control the expression of other genes by binding to their regulatory regions, and so can alter the type of proteins that are made by a cell. Thus the carefully coordinated pattern of gene expression and protein production that enables skeletal muscle to function effectively, is perturbed by the presence of DUX4. This ultimately leads to muscle weakness and wasting.We have examined gene expression changes during human muscle formation in FSHD cells and used mathematical tools to understand which signalling process are perturbed. We found that pathways that control generation of mitochondria and processes associated with mitochondrial function such as dealing with by-products of metabolism/respiration called reactive oxygen species (oxidative stress) are suppressed. It is well known that FSHD cells are more sensitive to oxidative stress, and a recent clinical trial (clinicaltrials.gov number: NCT01596803) reported that administration of anti-oxidants, improved aspects of muscle function in FSHD patients.We have found that inhibiting pathways that control generation of mitochondria in healthy human muscle cells makes them appear like FSHD muscle fibres. Conversely augmenting the action of these pathways controlling generation of mitochondria in FSHD muscle cells makes them more like healthy human muscle cells.This project will investigate how regulation of this pathway controlling generation of mitochondria is perturbed in FSHD and test potential therapeutic strategies to improve its function. 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, to underpin possible clinical trials. Better understanding the disease mechanism in FSHD may also highlight other potential therapeutic interventions.