Role of microRNA-206 in skeletal muscle regeneration

描述（由申请人提供）：骨骼肌在损伤后具有再生能力，并通过激活卫星细胞在出生后生长。控制卫星细胞功能的分子机制尚不完全清楚。近年来，研究发现microRNAs （miRNAs）通过促进mRNA降解和抑制mRNA翻译负向调控基因表达，参与肌肉细胞的应激反应，在肌肉发育和疾病中发挥重要作用。我们已经鉴定出9个mirna在心脏毒素诱导的骨骼肌损伤后上调，20个下调。我们计划研究这些mirna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，我们将重点关注显著诱导的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。miR-206敲除小鼠已经产生，可以存活，骨骼肌没有明显异常。使用这些突变小鼠，我们将评估miR-206在再生中的作用，并阐明介导这种反应的下游效应物。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，并通过操纵miRNA的表达和功能，促进肌肉修复的新治疗策略的发展。

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.