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。减少骨骼负荷会导致人类和大多数人的肌肉萎缩哺乳动物。废除肌肉萎缩代表了患者的重大临床问题长时间的固定和床休息。熊和地松鼠在很大程度上不活跃在休眠期间，它们的肌肉损失少于如此长时间的预期身体不活动的时期。这表明冬眠哺乳动物具有独特的自然适应肌肉骨骼废物。虽然在冬眠熊和地面上肌肉萎缩的衰减松鼠有充分的文献记载，这种重要适应的基础分子机制不是已知。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的表达和蛋白质合成的调节。我们的目标是通过microRNA表达和核糖体分析，候选microRNA和他们的目标成绩单，转化为蛋白质的成绩单以及代谢和信号通路在冬眠期间减少肌肉损失的能力是基础。为了实现这一目标，我们将完成以下特定目标（SA）。 SA1。分析MicroRNA表达曲线黑熊和北极地松鼠肌肉中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。利用跨不同状态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中的冬眠周期。完成后，全基因组microRNA 核糖体分析将检测到足够多的不同表达基因全面的途径分析阐明了转录变化的功能意义。我们期望比较共同调节基因的功能基因组和途径在两个具有不同冬眠模式的进化远处物种之间，揭示了一个共同的分子计划和可吸毒目标，用于未来研究和开发改进的治疗方法用于预防肌肉萎缩。