Molecular Mechanisms of Myoblast Fusion

成肌细胞融合的分子机制

基本信息

批准号：
8294038
负责人：
Elizabeth H Chen
金额：
$ 36.45万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294038
关键词：
Actins Animal Model Binding Biochemical Biochemistry Biology Candidate Disease Gene Cell physiology Cellular Structures Cellular biology Cicatrix Complex Data Degenerative Disorder Disease Drosophila genus Dynamin Dynamin 2 Dynamin III Embryo Employee Strikes Endocytosis Exhibits F-Actin Family Fingers Gelsolin Genes Genetic Goals Health Homologous Gene Human Invaded Lead Life Mammals Mediating Molecular Morphology Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscle satellite cell Mutation Myoblasts Myopathy Names Natural regeneration Neonatal Organ Orthologous Gene Patients Phosphotransferases Play Regulation Role Shapes Site Skeletal Muscle Structure System Therapeutic base cell type density fly human disease improved in vivo insight muscle degeneration muscle regeneration mutant myogenesis novel p21 activated kinase polymerization satellite cell therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Skeletal muscle is a unique organ that is composed of multinucleate muscle fibers, each of which is the product of fusion of hundreds or even thousands of myoblasts. Myoblast fusion is not only important for skeletal muscle development, but also critical for satellite cell-based muscle regeneration. Despite a large body of studies ove several decades, the mechanisms underlying myoblast fusion in humans remain poorly understood. Recent studies in the fruit fly Drosophila have begun to reveal unprecedented details about the molecular and cellular mechanisms of myoblast fusion. The striking evolutionary conservation between fly and mammalian myogenesis makes Drosophila a particularly relevant system to study myoblast fusion in vivo. Recent studies from our lab have uncovered a novel cellular mechanism underlying myoblast fusion. We show that myoblast fusion is mediated by a cell type-specific, F-actin-enriched podosome-like structure (PLS), which invades the opposing fusion partner with multiple protrusive fingers leading to fusion pore formation. To further characterize the regulation of the invasive PLS, the key cellular structure mediating myoblast fusion, we propose to investigate the molecular and cellular functions of two new genes, DPak3 and dynamin, both have previously been implicated in human diseases. We will use a multifaceted approach, including genetics, cell biology and biochemistry, to study the mechanisms by which DPak3 and dynamin regulate actin polymerization dynamics within the PLS in Drosophila myoblast fusion. We will also investigate the function of their mammalian orthologs in the fusion of mouse C2C12 myoblasts. Given the molecular and cellular conservation of myoblast fusion between fly and mammals, the proposed mechanistic studies using the simpler and genetically tractable Drosophila system will lead to significant insights int human muscle biology in health and disease, and ultimately provide a basis for developing more efficient therapeutics against the life debilitating muscle degeneration diseases. PUBLIC HEALTH RELEVANCE: Myoblast fusion is an essential step during skeletal muscle development and muscle stem cell-based regeneration. Understanding the mechanisms of myoblast fusion will lead to significant insights into human muscle biology in health and disease, and ultimately provide a basis for developing more efficient therapeutics against the life debilitating muscle degenerative diseases.

描述（由申请人提供）：骨骼肌是一个独特的器官，由多核肌肉纤维组成，每种肌肉纤维都是融合的产物数百甚至数千个肌细胞。成肌细胞融合不仅对骨骼肌发育很重要，而且对于基于卫星细胞的肌肉再生至关重要。尽管研究了数十年的大量研究，但人类成肌细胞融合的基础机制仍然很少理解。果蝇果蝇的最新研究已经开始揭示有关肌细胞融合的分子和细胞机制的前所未有的细节。苍蝇和哺乳动物肌发生之间的惊人进化保护使果蝇成为研究体内成肌细胞融合的特别相关系统。我们实验室的最新研究发现了肌细胞融合的一种新型细胞机制。我们表明，肌细胞融合是由细胞类型特异性的，富含F-肌动蛋白添加的型型型结构（PLS）介导的，该结构（PLS）用多种突出的手指侵入相反的融合伴侣，导致融合孔的形成。为了进一步表征侵入性PL的调节，介导成肌细胞融合的关键细胞结构，我们建议研究两个新基因DPAK3和Dynamin的分子和细胞功能，以前均与人类疾病有关。我们将使用一种多面方法，包括遗传学，细胞生物学和生物化学，研究DPAK3和Dynamin调节果蝇肌细胞融合中PLS中肌动蛋白聚合动力学的机制。我们还将研究其哺乳动物直系同源物在小鼠C2C12成肌细胞融合中的功能。鉴于苍蝇和哺乳动物之间的成肌细胞融合的分子和细胞保护，使用更简单和遗传上可触及的果蝇系统的拟议的机械研究将导致在健康和疾病中进行人体肌肉生物学的重要见解，并最终为针对生活中衰弱的肌肉变性疾病而开发更有效的治疗疗法。公共卫生相关性：肌细胞融合是骨骼肌发育和基于肌肉干细胞再生的重要步骤。了解成肌细胞融合的机制将导致对健康和疾病中人类肌肉生物学的重大见解，并最终为针对使生命衰弱的肌肉退行性疾病提供更有效的治疗疗法提供了基础。