Molecular Dissection of Myoblast Fusion In Muscle Development and Regeneration

肌肉发育和再生中成肌细胞融合的分子解剖

• 批准号: 9110820
• 负责人: RHONDA BASSEL-DUBY
• 金额: $ 35.54万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110820
• 关键词: Actins; Adult; Cell Culture Techniques; Cell fusion; Cell surface; Cells; Chimeric Proteins; Cytoskeleton; Development; Disease; Dissection; Drosophila genus; Embryo; Embryonic Development; Family; Fibroblasts; Foundations; Gene Deletion; Genetic; Glean; Goals; Health; Injury; Knowledge; Laboratories; Light; Membrane; Membrane Proteins; Molecular; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Muscle Proteins; Muscle satellite cell; Mutagenesis; Myoblasts; Myopathy; Names; Natural regeneration; Perinatal mortality demographics; Process; Proteins; Reagent; Signal Transduction; Skeletal Muscle; Specificity; Structure; System; Testing; Work; base; cell type; insight; interest; loss of function; muscle regeneration; novel; novel therapeutic intervention; novel therapeutics; overexpression; prevent; response to injury; restoration; satellite cell

 DESCRIPTION (provided by applicant): The formation of skeletal muscle during embryonic development and following injury to adult muscle requires fusion of myoblasts to form multinucleated myofibers. Recently, we discovered a novel muscle-specific membrane protein, named Myomaker, that controls vertebrate myoblast fusion during embryogenesis and adulthood. Myomaker is expressed on the cell surface of embryonic myoblasts during fusion and is down- regulated thereafter. Similarly, Myomaker is up-regulated in muscle satellite cells in response to injury, concomitant with their fusion during muscle regeneration. Over-expression of Myomaker in myoblasts dramatically enhances fusion and forced expression in fibroblasts promotes fusion with myoblasts. Conversely, genetic disruption of Myomaker in mice causes perinatal death due to an absence of multi- nucleated muscle fibers and conditional gene deletion in adult satellite cells completely prevents muscle regeneration. The discovery of Myomaker provides a new inroad into myoblast fusion and will enable the detailed molecular dissection of the mechanistic basis of this process. Myomaker belongs to a small family of related membrane proteins that are expressed in other cell types, suggesting a general mechanism for cell-cell fusion. The goals of this project are to define the precise molecular mechanism whereby Myomaker drives myoblast fusion and to identify additional components of the process through which Myomaker exerts its fusogenic activity. The insights gleaned from these studies will shed light not only on the fundamental mechanisms of intercellular fusion but will also have important implications for understanding muscle disease and for the potential development of new therapeutic strategies for restoration of function to diseased muscle.

 描述（申请人提供）：胚胎发育过程中骨骼肌的形成以及成年肌肉损伤后需要成肌细胞融合形成多核肌纤维最近，我们发现了一种新型肌肉特异性膜蛋白，称为Myomaker，它控制脊椎动物成肌细胞融合。在胚胎发生和成年期，Myomaker 在融合过程中在胚胎成肌细胞的细胞表面表达，并且随后下调。肌肉卫星细胞因损伤而上调，并在肌肉再生过程中发生融合。成肌细胞中 Myomaker 的过度表达可显着增强融合，成纤维细胞中的强制表达可促进与成肌细胞脱机融合，导致小鼠围产期的 Myomaker 基因破坏。由于成体卫星细胞中缺乏多核肌纤维和条件性基因删除而导致的死亡完全阻止了肌肉再生。Myomaker 的发现为肌肉再生提供了新的进展。 Myomaker 属于在其他细胞类型中表达的相关蛋白膜的一个小家族，这表明了细胞与细胞融合的一般机制。目的是定义 Myomaker 驱动成肌细胞融合的精确分子机制，并确定 Myomaker 发挥其融合活性的过程的其他组成部分，从这些研究中收集到的见解不仅将揭示细胞间的基本机制。融合也将对理解肌肉疾病以及潜在开发恢复患病肌肉功能的新治疗策略产生重要影响。