Ribosomal control of muscle mass: Transcriptional and epigenetic mechanisms

项目摘要 骨骼肌在整个生命周期的健康维护中起着重要作用。肌肉质量损失 可能具有长期的有害后果，导致康复期延长， mortality.肌肉的生长和维持在很大程度上取决于肌肉的合成能力 蛋白质，这反过来又受到肌肉核糖体的调节。核糖体的产生部分受转录控制 核糖体（r）RNA基因（rDNA）的RNA聚合酶I，并由转录抑制因子调节 Rb和p130。在这个提议中，我们试图了解Rb和p130的去除如何导致增强的 rRNA基因转录和肌肉肥大。使用一种新的动物模型，我们报告了令人兴奋的初步研究结果。 结果表明，Rb和p130基因的去除导致核糖体产生和骨骼肌生长的增强。 肌肉肥大利用这个和其他支持模型，我们将定义控制rRNA的新机制 通过研究转录和染色质重塑因子对基因表达的调节作用， rDNA的功能。这些研究将显著推进该领域，并为药物治疗产生新的靶点。 开发治疗方法，以防止肌肉质量和功能的丧失。

PROJECT SUMMARY Skeletal muscle plays a fundamental role in health maintenance throughout the lifespan. Loss of muscle mass can have long-lasting deleterious consequences leading to prolonged periods of convalescence and increased mortality. Muscle growth and maintenance are largely determined by the ability of the muscle to synthesize proteins, which in turn is regulated by muscle ribosome. Ribosome production is partly controlled by transcription of ribosomal (r)RNA genes (rDNA) by RNA Polymerase I, and is modulated by the transcriptional suppressors Rb and p130. In this proposal, we seek to understand how the removal Rb and p130 leads to enhanced transcription of rRNA genes and muscle hypertrophy. Using a novel animal model, we report exciting preliminary results indicating that genetic removal of Rb and p130 leads to enhanced ribosome production and skeletal muscle hypertrophy. Using this and other supporting models, we will define novel mechanisms controlling rRNA gene expression by studying the role of transcription and chromatin remodeling factors exerting modulatory functions on rDNA. These studies will significantly advance the field and generate novel targets for the development of therapies to prevent the loss of muscle mass and function.