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Deciphering mechanisms of myoblast fusion

破译成肌细胞融合机制

基本信息

批准号：
9099759
负责人：
Douglas Paul Millay
金额：
$ 34.32万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099759
关键词：
Actins Adhesions Adipose tissue Adult Amino Acids Biochemical Biochemical Genetics Cell Nucleus Cell Therapy Cell Transplantation Cell fusion Cell membrane Cells Cellular biology Chimeric Proteins Complement Complex Data Degenerative Disorder Development Ectopic Expression Endothelial Cells Extracellular Space Fibroblasts Foundations Genes Genetic Glypican Goals Health Heparan Sulfate Proteoglycan Immune In Vitro Integrins Knock-out Knowledge Mediating Membrane Membrane Fusion Membrane Proteins Modeling Molecular Muscle Muscle Cells Muscle Development Muscular Dystrophies Myoblasts Myopathy Names Natural regeneration Pathway interactions Process Proteins Proteomics Role Signal Transduction Skeletal Muscle Source System Therapeutic base cell type design functional restoration gain of function genetic approach in vivo in vivo Model insight muscle regeneration novel therapeutic intervention progenitor programs protein function repaired research study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Myoblast fusion is a fundamental process for proper skeletal muscle formation during development and regeneration. Despite the importance of myoblast fusion for muscle formation, the mechanisms that govern this process are not fully understood. Elucidation of fusion mechanisms is a critical step for understanding muscle development and to develop new therapeutic strategies to augment skeletal muscle disease. We recently discovered a muscle-specific protein, named myomaker, that localizes to the plasma membrane of myoblasts. Genetic deletion of myomaker during development and adult regeneration renders myoblasts fusion incompetent, which results in a dramatic inability to form skeletal muscle. Moreover, expression of myomaker in cells that normally do not express this protein causes their fusion with muscle cells. While myomaker is a central component for myoblast fusion, the regulatory mechanisms that govern its activity and the biochemical function of myomaker remain unknown. We have identified the regions of myomaker that are critical for its function and the proteins that interact with myomaker to potentially regulate its activity. In his project we will: 1) understand the function of myomaker within the fusion process 2) identify effectors of myomaker activity 3) evaluate the optimal cell type for heterologous fusion and myogenic reprogramming. We will use genetic loss-of- and gain-of-function approaches in vivo to investigate the role of myomaker during fusion. Extensive molecular approaches within our myomaker-based heterologous fusion system are proposed to identify the mechanisms that govern myomaker action. The ability of myomaker to drive fusion of heterologous cells with muscle cells will serve as the foundation to repair diseased skeletal muscle. We will use cell transplantation experiments to assess fusion and subsequent reprogramming of non-muscle cells with normal and diseased muscle. Successful completion of these aims will provide insight into the mechanisms of myoblast fusion by revealing how myomaker is regulated to induce membrane merger. Finally, these studies will have significant implications for a myomaker-mediated cell based strategy to rescue genetic muscle diseases.