Post transcriptional mechanisms of muscle atrophy prevention in hibernating mammals

项目摘要项目1--防止肌肉萎缩的转录后机制 在冬眠的哺乳动物身上。骨骼负荷减少导致人类和大多数人的肌肉萎缩 哺乳动物。废用性肌肉萎缩对患者来说是一个重要的临床问题 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，但他们表现出的肌肉损失比预期的如此长的时间要少 身体不活动的时期。这表明冬眠的哺乳动物有独特的自然适应。 到肌肉骨骼的废止。虽然冬眠熊和地面熊的肌肉萎缩程度有所减轻 松鼠是有充分证据的，但这种重要适应的分子机制却没有 为人所知。拟开展的研究主要集中在冬眠肌肉的转录后调控。 哺乳动物包括差异的microRNAs表达和蛋白质合成的调节。我们的 目标是通过microRNA表达和核糖体图谱识别候选microRNA和 他们的目标转录本，翻译成蛋白质的转录本，以及代谢和信号通路 这是在冬眠期间减少废用肌肉损失的基础。为了实现这一目标，我们将 实现以下特定目标(SA)。SA1.MicroRNA表达谱的分析 黑熊和北极地松鼠肌肉冬眠周期的不同状态。SA2. 北极地松鼠从头基因组组装的基因预测和注释。SA3. 利用核糖体图谱在蛋白质水平上分析不同状态下的基因表达 北极地松鼠肌肉的冬眠周期。一旦完成，全基因组的microRNA 核糖体图谱将检测到足够多的差异表达基因 综合途径分析阐明转录变化的功能意义。 我们期望对共同调控基因丰富的功能基因组和途径进行比较 在具有不同冬眠模式的两个进化的遥远物种之间揭示了一个共同的 未来改进治疗研究和开发的分子程序和可用药靶点 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.