GENETIC REGULATION OF SKELETAL MUSCLE REPAIR

骨骼肌修复的遗传调控

• 批准号: 2442853
• 负责人: Michael A Rudnicki
• 金额: $ 16.02万
• 依托单位: MCMASTER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2442853
• 关键词: cell differentiation; disease /disorder model; electron microscopy; genetic regulation; genetically modified animals; immunocytochemistry; laboratory mouse; muscular dystrophy; myoblasts; regeneration; striated muscles; transcription factor

DESCRIPTION: Gene targeting experiments have established unequivocally that the MyoD-family of transcription factors play key regulatory roles during embryonic skeletal-muscle development. By contrast, the role of the MyoD-family in adult skeletal muscle remains unclear. A role for MyoD in muscle regeneration is suggested by the observation that the MyoD is upregulated prior to satellite cell (the stem cell of adult muscle) proliferation and differentiation, and before expression of the remain factors. To test for a role for MyoD in muscle regulation,the investigator interbred MyoD mutant mice with the mdx mouse strain. The mdx mice are an animal model for Duchenne and Becker muscular dystrophies but unlike humans, skeletal muscle integrity is maintained by a high regenerative capacity. Their results indicate that mdx mice lacking MyoD display severe dystrophic changes in skeletal muscle leading to premature death around one year of age. They propose to further characterize by immunohistological and molecular analysis, the function of mutant, satellite cells in vivo and in vitro. To better understand the role played by MyoD, The investigator will examine skeletal muscle regeneration in mice overexpressing MyoD as a consequence of gene duplications generated by gene-targeting in embryonic stem cells. To investigate the mechanisms leading to satellite cell activation, they will examine expression of MyoD-LacZ transgenes to map the MyoD regulatory sequences required for this induction of MyoD transcription. This approach will also be used to determine the fate of satellite cells in mice lacking MyoD. Understanding how regulatory genes control the repair of skeletal muscle, in particular the formation, activation, proliferation, and terminal differentiation of satellite cells, is highly relevant to understanding the regenerative processes that occur in patients with different muscular dystrophies. Clearly, elucidating the function of MyoD in this regard should allow insights into the regeneration of skeletal muscle in health and disease, and potentially lead to novel therapies.

描述：基因靶向实验已明确确定 转录因子的myod家庭在 胚胎骨骼肌肉发育。 相比之下， 成年骨骼肌中的Myod家庭尚不清楚。 Myod的角色 肌肉再生是通过观察到myod是 在卫星细胞（成年肌肉的干细胞）之前上调 扩散和分化，以及在表达之前 因素。 为了测试Myod在肌肉调节中的作用，研究人员 与MDX小鼠菌株互化的Myod突变小鼠。 MDX小鼠是 Duchenne和Becker肌肉营养不良的动物模型，但与人不同， 骨骼肌完整性通过高再生能力维持。 他们的结果表明缺乏Myod显示的MDX小鼠严重营养不良 骨骼肌的变化导致过早死亡一年 年龄。 他们建议通过免疫组织学和 分子分析，突变体，体内卫星细胞的功能 体外。 为了更好地了解Myod的角色，调查员将 检查过表达Myod的小鼠的骨骼肌再生 胚胎中基因靶向产生的基因重复的结果 干细胞。 研究导致卫星细胞的机制 激活，他们将检查myod-lacz转基因的表达以绘制 诱导Myod转录所需的MYOD调节序列。 这种方法还将用于确定卫星细胞的命运 小鼠缺乏迈奥德。 了解调节基因如何控制修复 骨骼肌，特别是形成，激活，增殖和 卫星细胞的末端分化与 了解患者发生的再生过程 不同的肌肉营养不良。 显然，阐明了Myod的功能 在这方面，应该可以洞悉骨骼的再生 健康和疾病的肌肉，并有可能导致新的疗法。