Deciphering mechanisms of myoblast fusion

破译成肌细胞融合机制

• 批准号: 10818710
• 负责人: Douglas Paul Millay
• 金额: $ 24.08万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818710
• 关键词: Area; Cells; Cellular biology; Ectopic Expression; Fibroblasts; Goals; Investigation; Knowledge; Membrane; Membrane Proteins; Muscle; Muscle Development; Myoblasts; Myopathy; Process; Proteins; Reaction; Regenerative Medicine; Skeletal Muscle; System; Time; Work; improved; muscle physiology; muscle regeneration; novel; novel therapeutic intervention; progenitor; programs; reconstitution; Area; Cells; Cellular biology; Ectopic Expression; Fibroblasts; Goals; Investigation; Knowledge; Membrane; Membrane Proteins; Muscle; Muscle Development; Myoblasts; Myopathy; Process; Proteins; Reaction; Regenerative Medicine; Skeletal Muscle; System; Time; Work; improved; muscle physiology; muscle regeneration; novel; novel therapeutic intervention; progenitor; programs; reconstitution

Project Summary/Abstract Despite the importance of myoblast fusion for normal muscle development and physiology, relatively little is known about the molecules that directly function to remodel membranes during the myoblast fusion reaction. Elucidation of fusion mechanisms is critical to fully understand muscle development and to identify novel therapeutic strategies to augment skeletal muscle disease. We previously discovered that myomaker (Mymk) and myomerger (Mymx) are essential for the fusion of skeletal muscle progenitors. Moreover, ectopic expression of these two membrane proteins induces fusion of otherwise non-fusogenic cells (fibroblasts). For the first time, this establishes a cell-based reconstitution system with myoblast fusogens, however many questions exist as to how these two proteins induce fusion. We have recently found that myomaker and myomerger drive fusion through a unique cellular mechanism, by dividing their independent membrane remodeling activities to distinctly impact the fusion process. It stands to reason that the membrane-remodeling activities of myomaker and myomerger must be highly regulated or they could have the potential to compromise cellular integrity. With this supplement, we will expand our program to identify novel factors that regulate fusion in skeletal muscle tissue. Overall, this work promises to open up a new area of investigation into the cell biology of muscle and positively impact the possibility to harness fusion to improve regenerative medicine.

项目摘要/摘要 尽管肌细胞融合对于正常肌肉发育和生理学很重要，但相对较少的是 关于在成肌细胞融合反应期间直接重塑膜的分子已知。 阐明融合机制对于充分理解肌肉发育和识别新颖的机制至关重要 增加骨骼肌疾病的治疗策略。我们以前发现Myomaker（MyMK） 和Myomerger（MYMX）对于骨骼肌祖细胞的融合至关重要。而且，异位 这两种膜蛋白的表达诱导了原本非菌基因细胞（成纤维细胞）的融合。为了 第一次，这是用成肌细胞固定物建立基于细胞的重构系统，但是许多 关于这两种蛋白如何诱导融合的问题存在问题。我们最近发现Myomaker和 Myomerger驱动融合通过独特的细胞机制，通过分开其独立膜 重塑活动以明显影响融合过程。有理由认为膜变形 Myomaker和Myomerger的活动必须受到高度监管，否则它们可能有可能 损害细胞完整性。有了这种补充，我们将扩大我们的计划，以确定新的因素 调节骨骼肌组织中的融合。总体而言，这项工作有望开放新的调查领域 进入肌肉的细胞生物学，并积极影响利用融合的可能性，以改善再生 药品。