Post transcriptional mechanisms of muscle atrophy prevention in hibernating mammals

冬眠哺乳动物预防肌肉萎缩的转录后机制

基本信息

批准号：
10659069
负责人：
Vadim Fedorov
金额：
$ 19.59万
依托单位：
UNIVERSITY OF ALASKA FAIRBANKS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-16 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659069
关键词：
Arousal Bed rest Black Bear Catabolism Clinical Data Development Distant Follow-Up Studies Foundations Future Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Genetic Transcription Genome Goals Hibernation Human Immobilization Light Mammals Maps Metabolic Pathway Metabolism MicroRNAs Modeling Molecular Muscle Muscular Atrophy Musculoskeletal Nucleotides Pathway Analysis Pathway interactions Patients Post-Transcriptional Regulation Prevention Process Protein Biosynthesis Proteins Regulation Regulator Genes Rehabilitation therapy Research Ribosomes Signal Pathway Skeletal Muscle Skeleton Spermophilus Testing Transcript Translating Translations arctic ground squirrel attenuation differential expression druggable target genome-wide improved mRNA Translation mechanical load miRNA expression profiling muscle form muscle strength next generation sequencing novel strategies overexpression physical inactivity posttranscriptional preservation programs reference genome ribosome profiling skeletal therapeutic target transcriptome

项目摘要

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.

项目摘要项目1——预防肌肉萎缩的转录后机制在冬眠的哺乳动物中，骨骼负荷的减少会导致人类和大多数动物的肌肉萎缩。废用性肌肉萎缩对哺乳动物来说是一个重要的临床问题。长时间不动和卧床休息熊和地松鼠基本上不活动。在冬眠期间，但它们表现出的肌肉损失比在如此长时间的冬眠期间预期的要少这表明冬眠哺乳动物具有独特的自然适应能力。虽然冬眠的熊和地面的肌肉萎缩会减弱。松鼠有充分的记录，但这种重要适应的分子机制尚不清楚已知拟议的研究重点是冬眠肌肉的转录后调节。哺乳动物，包括差异 microRNA 表达和蛋白质合成的调节。目标是通过 microRNA 表达和核糖体分析来识别候选 microRNA 和它们的目标转录本、翻译成蛋白质的转录本以及代谢和信号传导途径减少冬眠期间废用性肌肉损失的能力是实现这一目标的基础。完成 SA1 中 microRNA 表达谱的以下特定目标 (SA)。黑熊和北极地松鼠 SA2 肌肉冬眠周期的不同状态。北极地松鼠 SA3 基因组从头组装的基因预测和注释。使用不同状态下的核糖体分析在蛋白质水平上分析基因表达北极地松鼠肌肉的冬眠周期一旦完成，全基因组 microRNA 就会出现。核糖体分析将检测足够多的差异表达基因全面的通路分析阐明了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两个具有不同冬眠模式的进化遥远物种之间的研究揭示了一个共同点用于未来研究和开发改进治疗的分子计划和药物靶点用于和预防废用性肌肉萎缩。