Targeting calcineurin for improving muscle regeneration in skeletal muscle disease

肌营养不良是一个术语，涵盖了一组不同的遗传性疾病，其特征是进行性肌肉无力和消瘦。杜氏肌营养不良症（DMD）是最严重的形式，由缺乏一种称为肌营养不良蛋白的蛋白质引起，这种蛋白质使肌肉脆弱，易受损伤，并且损伤后再生或修复能力受损。这种疾病会发展到所有的肌肉，DMD患者在十几岁之前就依赖于轮椅，并在二十多岁时死亡。对于可以改善营养不良状况并改善患者生活质量的治疗存在深刻的需求。恢复或增加肌肉的再生能力将有助于改善肌肉功能。我们有令人信服的证据表明，钙调磷酸酶信号转导通路是重要的成功肌肉再生的小鼠肌营养不良症。在世界范围内，刺激钙调神经磷酸酶可以减轻营养不良的病理学，然而，对钙调神经磷酸酶信号传导在人类肌肉疾病中的作用知之甚少。我们的目标是研究钙调磷酸酶信号在肌营养不良症中的作用，并研究其增强肌肉再生的治疗潜力。我们的目的是更好地了解机制控制钙调磷酸酶信号在肌肉营养不良的小鼠和肌肉DMD患者。将进行一系列全面的生理，分子，生化和免疫组织化学实验，以严格测试我们的研究目标。了解钙调神经磷酸酶途径在肌肉再生中的作用对于开发新的治疗策略以延迟肌肉萎缩和虚弱的发作或减缓其进展是重要的。这些发现将对我们理解与其他疾病相关的肌营养不良症具有广泛的临床应用，包括衰老，艾滋病，烧伤，癌症恶病质和废用性萎缩，其中发生肌肉萎缩。

Muscular dystrophy is a term that covers a diverse group of inherited disorders characterised by progressive muscle weakness and wasting. Duchenne muscular dystrophy (DMD) is the most severe form, caused by a lack of a protein called dystrophin, which renders muscles fragile, susceptible to damage, and with a compromised ability to regenerate or repair after injury. The disease progresses to all muscles and DMD patients are dependent on a wheelchair before their early teens and die in their twenties. There is a profound need for treatments that can ameliorate the dystrophic condition and improve patient quality of life. Restoring or increasing a muscle's capacity to regenerate would help improve muscle function. We have convincing evidence that the calcineurin signal transduction pathway is important for successful muscle regeneration in mice with muscular dystrophy. There is growing excitement worldwide that stimulating calcineurin could attenuate the dystrophic pathology, however, little is known about the role of calcineurin signalling in human muscle disease. Our goals are to investigate the role of calcineurin signalling in muscular dystrophy and to examine its therapeutic potential for enhancing muscle regeneration. Our aim is to better understand the mechanisms controlling calcineurin signalling in muscles of dystrophic mice and in muscles of patients with DMD. A comprehensive series of physiological, molecular, biochemical, and immunohistochemical experiments will be performed to rigorously test our research aim. Understanding the role of the calcineurin pathway in muscle regeneration is important for the development of novel therapeutic strategies to delay the onset or slow the progression of muscle wasting and weakness. The findings will have broad clinical application for our understanding of muscular dystrophy with relevance to other conditions including ageing, AIDS, burns, cancer cachexia, and disuse atrophy, where muscle wasting occurs.