FOR 1228: Molecular Pathogenesis of Myofibrillar Myopathies

肌原纤维性肌病是一种进行性和破坏性的人类骨骼肌疾病，经常导致过早死亡。到目前为止，没有病因或改善治疗。肌原纤维性肌病的组织病理学特征为病理性蛋白质聚集和肌原纤维的退行性变化。而这些进行性肌肉疾病的一半是由结蛋白-，细丝蛋白C-，凝集素-，VCP-，FHL1-，ZASP-，肌球蛋白-，？晶体蛋白和BAG3基因突变，另一半肌原纤维性肌病是由于尚未解决的基因缺陷。从单个基因缺陷到骨骼肌组织共同结构病理的精确分子途径目前尚不清楚。本研究单位的重点是以下目标：（1）由于结蛋白-，凝集素-，细丝蛋白C-，ZASP-，VCP-，FHL 1-和？B-晶状体蛋白突变;（2）疾病特异性细胞和动物模型的系统分析;（3）用于药理学治疗策略的细胞和动物模型的验证;（4）来自肌原纤维肌病患者和疾病相关动物模型的骨骼肌活检中病理性蛋白质聚集体的组成的生物化学表征;（5）鉴定新的基因和蛋白质，其主要参与肌原纤维性肌病的发病机制。该研究单位由来自八所不同大学的杰出团队驱动，将专门分析肌原纤维肌病的发病机制。这项工作将是新的有针对性的治疗方法的基础上，这个重要的队列遗传性肌病。

Myofibrillar myopathies are progressive and devastating diseases of the human skeletal muscle that often lead to premature death. To date, no causative or ameliorating therapy is available. Myofibrillar myopathies are histopathologically characterised by pathological protein aggregates and degenerative changes of myofibrills. While half of these progressive muscle diseases are caused by desmin-, filamin C-, plectin-, VCP-, FHL1-, ZASP-, myotilin-, ?B-crystallin and BAG3-gene mutations, the other half of Myofibrillar myopathies is due to still unresolved gene defects. The precise molecular pathways leading from an individual gene defect to a mutually shared structural pathology of skeletal muscle tissue are currently unknown. This Research Unit focusses on the following goals: (1) characterisation of individual and shared disease mechanisms in myofibrillar myopathies due to desmin-, plectin-, filamin C-, ZASP-, VCP-, FHL1- and ?B-crystallin mutations; (2) systematic analyses of disease-specific cell and animal models; (3) validation of cell and animal models for pharmacological treatment strategies; (4) biochemical characterisation of the composition of pathological protein aggregates in skeletal muscle biopsies from patients with myofibrillar myopathies and disease relevant animal models; (5) identification of novel genes and proteins that are centrally involved in the pathogenesis of myofibrillar myopathies. This Research Unit, which is driven by distinguished groups from eight different universities, will specifically analyse the pathogenesis of myofibrillar myopathies. This work will be the basis for novel targeted treatment approaches for this significant cohort of hereditary myopathies.