New therapy strategies for desmin-related myopathies and cardiomyopathies

结蛋白相关肌病和心肌病的新治疗策略

• 批准号: 469329358
• 负责人: Professor Dr. Christoph S. Clemen
• 金额: --
• 依托单位: Institut für Luft- und Raumfahrtmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/469329358?language=en
• 关键词: New; therapy; strategies; desmin; related

Desmin is an intermediate filament protein, which is an essential component of the extra-sarcomeric cytoskeleton in striated muscle cells. The pivotal role of desmin is highlighted by the observation that mutations of the human desmin gene on chromosome 2q35 cause a clinically diverse group of autosomal-dominantly and -recessively inherited as well as sporadic myopathies and cardiomyopathies. To date neither specific nor ameliorating therapies are available for this group of progressive, severely disabling, and often premature lethal diseases. Based on our comprehensive work on the pathophysiology of desminopathies employing muscle tissue specimens from patients and from our desminopathy mouse models, we here plan to conduct an experimental, pre-clinical study addressing new therapeutic strategies. For this purpose, we will analyze the effects of acute and chronic physical exercise as well as of a pharmacological treatment with two repositioned drug candidates, i.e., the chemical chaperone 4-phenylbutyrate and the anti-oxidant N-acetylcysteine, in hetero- and homozygous R349P desmin knock-in and homozygous desmin knock-out mice. Specifically, we will address the following key questions: i) Is acute, strenuous treadmilling harmful to skeletal and cardiac muscle tissue in desminopathies? ii) To what extent is chronic, low-intensity treadmilling beneficial for striated muscle in desminopathies? iii) Does the application of 4-phenylbutyrate or N-acetylcysteine improve muscle strength or morphology in desminopathies? This project has the translational potential to improve the counselling of affected humans with regard to effects of physical activity. Moreover, our drug repositioning approach may provide the basis for a first pharmacological treatment in human desminopathy patients.

结蛋白是一种中间丝蛋白，是横纹肌细胞肌节外细胞骨架的重要组成部分。染色体2 q35上的人结蛋白基因的突变引起常染色体显性遗传和隐性遗传以及散发性肌病和心肌病的临床多样性组的观察突出了结蛋白的关键作用。迄今为止，对于这组进行性、严重致残且通常过早致死的疾病，既没有特异性治疗也没有改善性治疗。基于我们对结蛋白病的病理生理学的全面研究，我们采用了来自患者的肌肉组织标本和来自我们的结蛋白病小鼠模型，我们在这里计划进行一项实验性的临床前研究，以解决新的治疗策略。为此，我们将分析急性和慢性体育锻炼以及两种重新定位的候选药物的药理学治疗的效果，即，化学伴侣4-苯基丁酸和抗氧化剂N-乙酰半胱氨酸，在杂合和纯合R349 P结蛋白敲入和纯合结蛋白敲除小鼠中。具体来说，我们将解决以下关键问题：i）急性，剧烈的研磨对结蛋白病的骨骼和心肌组织有害吗？ii）慢性低强度磨铣在多大程度上有利于结蛋白病患者的横纹肌？iii）4-苯基丁酸或N-乙酰半胱氨酸的应用是否改善结蛋白病中的肌肉力量或形态？该项目具有转化潜力，可以改善受影响人群在体力活动影响方面的咨询。此外，我们的药物重新定位方法可能为人类结蛋白病患者的首次药物治疗提供基础。