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: 9301471
• 负责人: RHONDA BASSEL-DUBY
• 金额: $ 35.64万
• 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/9301471
• 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; 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; Pharmacology; 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; public health relevance; 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（由适用提供）：胚胎发育过程中骨骼肌的形式和成年肌肉受伤后需要融合成肌细胞以形成多核肌纤维。最近，我们发现了一种新型的肌肉特异性膜蛋白，称为Myomaker，该蛋白在胚胎发生和成年期间控制脊椎动物肌细胞融合。在融合过程中，在胚胎成肌细胞的细胞表面上表达了肌瘤制剂，此后被下调。同样，在肌肉卫星细胞中，肌球员在响应损伤的肌肉卫星细胞中也被上调，并在肌肉再生过程中融合。成肌细胞中肌成肌制剂的过表达极大地增强了成纤维细胞中的融合和强迫表达可促进与肌细胞的融合。相反，由于缺乏多核肌肉纤维和成年卫星细胞中有条件的基因缺失，小鼠肌瘤者的遗传破坏会导致围产期死亡，这完全阻止了肌肉再生。 Myomaker的发现为肌细胞融合提供了新的进攻，并将使该过程的机械基础的详细分子解剖。 Myomaker属于在其他细胞类型中表达的一小部分相关膜蛋白，这表明了细胞 - 细胞融合的一般机制。该项目的目标是定义精确的分子机制，从而使肌细胞驱动成肌细胞融合并确定肌莫制蛋白酶发挥其融合活性的过程的其他组成部分。从这些研究中收集的见解不仅会阐明细胞间融合的基本机制，而且还将对理解肌肉疾病以及对恢复功能恢复肌肉的新治疗策略的潜在发展具有重要意义。