Collagen VI assembly and function in musculoskeletal disorders

肌肉骨骼疾病中 VI 型胶原蛋白的组装和功能

• 批准号: 407164210
• 负责人: Professor Dr. Mats Paulsson
• 金额: --
• 依托单位: Klinik und Poliklinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/407164210?language=en
• 关键词: Collagen; VI; assembly; function; musculoskeletal

Collagen VI is a microfibrillar protein of the extracellular matrix with ubiquitous tissue distribution. Mutations in the genes encoding the three major collagen VI chains (COL6A1, COL6A2 and COL6A3) cause a group of myopathies of varying severity, including Bethlem myopathy and Ullrich congenital muscular dystrophy. Studies in patients and mouse models have unveiled pathognomonic features of collagen VI deficient muscles such as increased spontaneous apoptosis of myofibres, mitochondrial dysfunction, deficient autophagy and reduced regenerative potential. However, the exact mechanisms linking collagen VI deficiency to these specific cellular defects are still elusive. In this project, using a combination of high-throughput and high-resolution analysis, we aim to characterize the biochemical signals conveyed by collagen VI and to identify the cell populations that respond to these signals in vivo within skeletal muscles. Finally, we will describe at the single-cell level how mutations in this extracellular matrix protein are translated in specific cellular defects, and ultimately, in the loss of musculoskeletal tissue homeostasis. Our goal is to push forward our understanding of these human muscular disorders providing new information that can help the development of novel therapeutic approaches.

胶原VI是细胞外基质的微纤维蛋白，具有普遍的组织分布。编码三种主要胶原VI链（COL6A1、COL6A2和COL6A3）的基因突变会导致一组严重程度不同的肌病，包括Bethlem肌病和Ullrich先天性肌营养不良症。对患者和小鼠模型的研究揭示了VI型胶原蛋白缺乏肌肉的特征，如肌纤维自发凋亡增加、线粒体功能障碍、自噬缺陷和再生潜力降低。然而，将胶原VI缺乏与这些特定细胞缺陷联系起来的确切机制仍然难以捉摸。在这个项目中，使用高通量和高分辨率分析的组合，我们的目标是表征VI型胶原蛋白传递的生化信号，并确定在骨骼肌内体内对这些信号作出反应的细胞群。最后，我们将在单细胞水平上描述这种细胞外基质蛋白的突变是如何在特定的细胞缺陷中翻译的，并最终导致肌肉骨骼组织稳态的丧失。我们的目标是推动我们对这些人类肌肉疾病的理解，提供新的信息，可以帮助开发新的治疗方法。