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Biochmechanics of MFM: a multi-scale approach

MFM 的生物力学：多尺度方法

基本信息

批准号：
228081227
负责人：
Professor Dr. Ben Fabry
金额：
--
依托单位：
Lehrstuhl für Medizinische Biotechnologie (MBT)
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/228081227?language=en
关键词：
Biochmechanics MFM multi scale approach

项目摘要

Myofibrillar myopathies (MFM) are associated with mutations in genes encoding cytoskeletal proteins and linker proteins, e.g. desmin or plectin. Most of these proteins connect adjacent myofibrils as well as myofibrils to Z-lines or other important cytoskeletal components and thus, ensure proper anchorage in biomechanically active muscle. Disruptions of these linkages are expected to result in vast disturbances of biomechanical properties, including elasticity, active force production, lower mechanical stress resistance that can induce cell damage and insufficient repair. Although the common symptom in all patients with MFM is muscle weakness, there is almost no information at hand as to how muscle is affected at different structural and functional levels within the organ and what is the molecular cause of the muscle weakness. The present Z-Project unites a consortium of researchers with renowned expertise in muscle biomechanics at all levels of organ function. In a multiscale approach, we will systematically investigate active and passive biomechanical properties of muscle function at the level of whole muscles, small muscle fibre bundles and single muscle fibres as well as biomechanical response to cyclic stretch and focal adhesion points in primary myoblasts. Using the established mouse models within FOR1228 (Des-KO, DesR350P-KI hetero-/homozygous, conditional Plct-MCKCRE7cKO, isoform-specific Plct-KO P1b/P1d) as well as samples from MFM patients, our aim is to identify biomechanical dysfunction several structural levels. Furthermore, we will test the hypothesis that MFM share common functional patterns despite their underlying molecular heterogeneity.

肌原纤维性肌病（MFM）与编码细胞骨架蛋白和连接蛋白（如desmin或plectin）的基因突变有关。这些蛋白质中的大多数将相邻的肌原纤维以及肌原纤维连接到z线或其他重要的细胞骨架成分，从而确保在生物力学活跃的肌肉中适当地锚固。这些连接的破坏预计会导致生物力学特性的巨大干扰，包括弹性、主动力产生、机械应力抵抗能力降低，从而导致细胞损伤和修复不足。虽然所有MFM患者的共同症状是肌肉无力，但几乎没有关于器官内不同结构和功能水平的肌肉是如何受到影响的信息，以及肌肉无力的分子原因是什么。目前的Z-Project联合了一个研究人员联盟，他们在各个器官功能水平的肌肉生物力学方面都有著名的专业知识。在多尺度方法中，我们将系统地研究肌肉功能在整个肌肉、小肌纤维束和单个肌纤维水平上的主动和被动生物力学特性，以及原发性成肌细胞对循环拉伸和焦点粘附点的生物力学响应。利用已建立的FOR1228小鼠模型（Des-KO， DesR350P-KI异/纯合子，条件Plct-MCKCRE7cKO，同种型特异性Plct-KO P1b/P1d）以及MFM患者样本，我们的目标是确定几个结构水平的生物力学功能障碍。此外，我们将验证MFM具有共同功能模式的假设，尽管它们潜在的分子异质性。