Collagen VI assembly and function in musculoskeletal disorders

VI型胶原是细胞外基质中的一种微纤维蛋白，在组织中广泛分布。编码三个主要胶原VI链(COL6A1、COL6A2和COL6A3)的基因突变会导致一组不同严重程度的肌肉疾病，包括Bethlem肌病和Ullrich先天性肌营养不良。在患者和小鼠模型上的研究揭示了VI型胶原缺陷肌肉的病因学特征，如肌纤维自发性凋亡增加，线粒体功能障碍，自噬功能缺陷和再生潜力降低。然而，VI型胶原缺乏与这些特定的细胞缺陷之间的确切机制仍不清楚。在这个项目中，结合高通量和高分辨率分析，我们的目标是表征VI型胶原所传递的生化信号，并识别体内骨骼肌中对这些信号做出反应的细胞群。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如何转化为特定的细胞缺陷，并最终导致肌肉骨骼组织动态平衡的丧失。我们的目标是推动我们对这些人类肌肉疾病的理解，提供有助于开发新的治疗方法的新信息。

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.