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Understanding and Ameliorating perturbed signalling and pathogenesis in FSHD

了解和改善 FSHD 中的扰动信号传导和发病机制

基本信息

批准号：
MR/S002472/1
负责人：
Peter Zammit
金额：
$ 49.02万
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：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS002472%2F1
关键词：
Understanding Ameliorating perturbed signalling pathogenesis

项目摘要

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.

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，致病缺陷是基因或DNA的变化，反过来，产生蛋白质的变化。然而，人们通常对这种缺陷如何导致肌营养不良症典型的进行性骨骼肌无力和消瘦知之甚少。身体中的每个细胞都含有相同的DNA，DNA分为基因，每个基因都携带制造蛋白质的指令：构建，维护和操作身体的分子。选择在特定细胞类型（如肌肉纤维）中表达（活性）的基因，决定了哪些蛋白质被制造出来。这赋予了细胞特殊的特性和功能。面肩肱型肌营养不良症（FSHD）是由DNA的一个特定区域发生变化，导致产生一种称为DUX 4的蛋白质，这种蛋白质通常不存在于肌肉中。DUX 4是一种“转录因子”，这意味着它可以通过与其他基因的调控区结合来控制其他基因的表达，因此可以改变细胞产生的蛋白质的类型。因此，使骨骼肌有效发挥功能的基因表达和蛋白质生产的精心协调模式被DUX 4的存在所扰乱。这最终导致肌肉无力和wasting.We检查了基因表达的变化在人类肌肉形成FSHD细胞和使用数学工具来了解哪些信号传导过程受到干扰。我们发现，控制线粒体生成的途径和与线粒体功能相关的过程，如处理代谢/呼吸的副产物（称为活性氧（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：NCT 01596803）报道，抗氧化剂的施用改善了FSHD患者肌肉功能的各个方面。我们发现，抑制健康人类肌肉细胞中控制线粒体生成的途径，使它们看起来像FSHD肌肉纤维。相反，增强这些控制FSHD肌细胞中线粒体生成的途径的作用，使它们更像健康的人类肌细胞。本项目将研究FSHD中控制线粒体生成的途径的调节如何受到干扰，并测试潜在的治疗策略以改善其功能。因此，总之，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的潜在疗法提供平台，以支持可能的临床试验。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。