Accelerated and programmed mRNA decay by AU-rich binding protein AUF1 in the regulation of muscle regeneration

项目摘要 目前，人们对骨骼肌干细胞(称为卫星细胞)的潜力非常感兴趣。 用于再生性组织治疗。骨骼肌干细胞的分子理解 维持、命运决定和分化是将研究转化为治疗的关键 退行性肌肉疾病，几乎没有有效的治疗选择。这份提案调查了 肌肉干细胞的维持、更新和再生计划是由选择性的， 在AUF1蛋白的引导下加速了mRNA的衰退。这是一个非常重要但在很大程度上未被研究的 在编程和控制成人组织干细胞命运方面发挥主要作用的基因调控领域 组织再生。我们在以前研究的基础上，建议确定调节AUF1的因素 在卫星细胞中的表达，因为AUF1协调卫星的肌肉再生程序 细胞，识别AUF1选择性地快速降解的卫星细胞mRNAs，因为这看起来 上演肌肉再生的不同发育事件，以及AUF1如何协调 通过与关键调控蛋白相互作用重新编程的进展，因为这控制着命运 卫星细胞从激活到肌肉再生的测定。

Project Summary There is currently significant interest in the potential for skeletal muscle stem cells, known as satellite cells, to be used in regenerative tissue therapy. The molecular understanding of skeletal muscle stem cell maintenance, fate determination and differentiation is crucial for translating research to the treatment of degenerative muscle diseases where there are few effective treatment options. This proposal investigates how the program of muscle stem cell maintenance, renewal and regeneration are orchestrated by selective, accelerated mRNA decay directed by the protein AUF1. This is a highly important but largely understudied area of gene regulation that plays a major role in programming and controlling adult tissue stem cell fate and tissue regeneration. We build on our previous studies and propose to identify the factors that regulate AUF1 expression in the satellite cell because AUF1 orchestrates the muscle regeneration program of the satellite cell, identify the satellite cell mRNAs selectively targeted for rapid degradation by AUF1 because this appears to stage the different developmental events of muscle regeneration, and how AUF1 orchestrates the progression of reprogramming by interacting with key regulatory proteins because this controls fate determination of satellite cells from activation to muscle regeneration.