Role of microRNA-206 in skeletal muscle regeneration

描述(申请人提供)：骨骼肌具有损伤后再生和通过激活卫星细胞在出生后生长的能力。控制卫星细胞功能的分子机制尚不完全清楚。近年来发现，microRNAs(MiRNAs)通过促进mRNA降解和抑制mRNA翻译来负向调节基因的表达，在肌肉细胞的应激反应中发挥作用，在肌肉发育和疾病中发挥重要作用。我们已经鉴定出9个心脏毒素诱导的骨骼肌损伤后上调的miRNAs和20个下调的miRNAs。我们计划研究一些这样的miRNAs在再生过程中的作用。为了实现这一目标，我们将使用体外方法结合基因敲除和转基因小鼠模型。特别是，我们将关注显著诱导的miR-206(心脏毒素损伤后增加16倍)在骨骼肌再生和重塑中的作用。已经产生了MIR-206基因敲除小鼠，可以存活，并且在骨骼肌中没有表现出明显的异常。利用这些突变的小鼠，我们将评估miR-206在再生中的作用，并阐明介导这一反应的下游效应因子。这些研究将为肌肉疾病和再生的病理生理学提供新的见解，并将促进通过操纵miRNA的表达和功能来开发新的肌肉修复治疗策略。 与公共卫生相关：该项目的总体目标是阐明在损伤和再生反应中调节microRNA-206表达的机制，并确定介导这些过程的miR-206靶标。这些研究将为肌肉疾病和再生的病理生理学提供新的见解，并将促进通过操纵miRNA的表达和功能来开发新的肌肉修复治疗策略。

DESCRIPTION (provided by applicant): Skeletal muscle possesses the ability to regenerate after injury and grow postnatally through the activation of satellite cells. The molecular mechanisms which control satellite cell function are not completely understood. Recently, it has been revealed that microRNAs (miRNAs), which negatively regulate gene expression by promoting mRNA degradation and inhibiting mRNA translation, function in the stress response of muscle cells and play important roles in muscle development and disease. We have identified 9 miRNAs which are up-regulated after cardiotoxin-induced skeletal muscle injury and 20 which are down-regulated. We plan to investigate the role of a number of these miRNAs in the regenerative process. To achieve this goal we will use in vitro approaches in conjunction with knockout and transgenic mouse models. In particular, we will focus on the role of the dramatically induced miR-206 (16-fold increase after cardiotoxin injury) in skeletal muscle regeneration and remodeling. miR-206 knockout mice have been generated, are viable, and exhibit no gross abnormalities in skeletal muscle. Using these mutant mice we will assess the role of miR-206 in regeneration and elucidate the downstream effectors which mediate this response. These studies will provide new insights into the pathophysiology of muscle disease and regeneration, and should also facilitate the development of new therapeutic strategies for muscle repair through the manipulation of miRNA expression and function. PUBLIC HEALTH RELEVANCE: The overall aim of this project is to elucidate the mechanisms that regulate microRNA-206 expression in response to injury and regeneration and to define the targets of miR-206 that mediate these processes. These studies will provide new insights into the pathophysiology of muscle disease and regeneration, and should also facilitate the development of new therapeutic strategies for muscle repair through the manipulation of miRNA expression and function.