Post transcriptional mechanisms of muscle atrophy prevention in hibernating mammals

项目概要项目1 -肌肉萎缩预防的转录后机制 冬眠的哺乳动物骨骼负荷减少导致人类肌肉萎缩， 哺乳动物废用性肌肉萎缩代表了患者在治疗过程中的一个重要临床问题。 长时间的固定和卧床休息。熊和地松鼠基本上不活动 在冬眠期间，但它们的肌肉损失比预期的要少， 一段时间的身体不活动。这表明冬眠的哺乳动物有独特的自然适应能力 到肌肉骨骼废用虽然冬眠的熊和地面的肌肉萎缩的衰减 松鼠的这种重要适应的分子机制已经有据可查，但还没有 知道的本文拟对冬眠动物肌肉中的转录后调控进行研究 哺乳动物，包括差异microRNA表达和蛋白质合成的调节。我们 目的是通过microRNA表达和核糖体分析，鉴定候选microRNA， 它们的目标转录物，翻译成蛋白质的转录物，以及代谢和信号通路， 在冬眠期间减少废用性肌肉损失的能力。为了实现这一目标，我们将 实现以下具体目标（SA）。SA 1.跨物种microRNA表达谱分析 黑熊和北极地松鼠肌肉冬眠周期的不同状态。SA 2. 北极地松鼠基因组从头组装的基因预测与注释。SA 3. 在蛋白质水平上使用核糖体谱分析跨细胞的不同状态的基因表达， 北极地松鼠肌肉中的冬眠周期。一旦完成，全基因组microRNA 核糖体分析将检测足够大数量的差异表达基因， 全面的途径分析阐明了转录变化的功能意义。 我们期望比较功能基因组和途径丰富的共调控基因 两个具有不同冬眠模式的进化遥远物种之间的差异揭示了一个共同点 未来研究和开发改进治疗的分子程序和药物靶点 用于和预防废用性肌肉萎缩。

Project Summary Project 1 – Post-transcriptional mechanisms of muscle atrophy prevention in hibernating mammals. Reduced skeletal loading leads to muscle atrophy in humans and most mammals. Disuse muscle atrophy represents a significant clinical problem for patients during prolonged periods of immobilization and bed rest. Bears and ground squirrels are largely inactive during hibernation, but they show less muscle loss than would be anticipated over such a prolonged period of physical inactivity. This suggests that hibernating mammals have unique natural adaptation to musculoskeletal disuse. Although attenuation of muscle atrophy in hibernating bears and ground squirrels is well documented, molecular mechanisms underlying this important adaptation are not known. The proposed research focuses on post-transcriptional regulation in muscle of hibernating mammals that includes differential microRNAs expression and regulation of protein synthesis. Our goal is to identify, through microRNA expression and ribosome profiling, candidate microRNAs and their target transcripts, transcripts translated to proteins, and metabolic and signaling pathways that underlie the ability to reduce disuse muscle loss during hibernation. To achieve this goal we will accomplish the following Specific Aims (SA). SA1. Analysis of microRNA expression profiles across different states of the hibernation cycle in muscle of the black bear and arctic ground squirrel. SA2. Gene prediction and annotation of de novo genome assembly of the arctic ground squirrel. SA3. Analysis of gene expression at the protein level using ribosome profiling across different states of the hibernation cycle in muscle of the arctic ground squirrel. Once completed, genome-wide microRNA and ribosome profiling will detect sufficiently large number of differentially expressed genes for comprehensive pathway analysis elucidating the functional significance of transcriptional changes. We expect comparison of functional gene groups and pathways enriched by co-regulated genes between two evolutionary distant species with different hibernation modes to reveal a common molecular program and druggable targets for future study and development of improved treatments for and prevention of disuse muscle atrophy.