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Ribosomal control of muscle mass: Transcriptional and epigenetic mechanisms

核糖体控制肌肉质量：转录和表观遗传机制

基本信息

批准号：
10683335
负责人：
Gustavo A Nader
金额：
$ 34.8万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683335
关键词：
Ablation Aging Animal Model Biology Chromatin Chromatin Remodeling Factor Chronic Chronic Disease Complex Convalescence DNA Polymerase I Data Deacetylation End stage renal failure Environment Enzymes Epigenetic Process Excision Gene Dosage Gene Expression Genes Genetic Genetic Transcription Goals Growth HDAC1 gene Health Human Hypertrophy In Vitro Knowledge Longevity Maintenance Malignant Neoplasms Mediating Methylation Modeling Molecular Molecular Chaperones Molecular Target Morphology Muscle Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Outcome Study Play Production Protein Biosynthesis RNA RNA Polymerase I Relaxation Reporting Repression Resistance Retinoblastoma Protein Ribosomal DNA Ribosomes Rodent Role Series Skeletal Muscle Stress Testing cancer cachexia chromatin modification chromatin remodeling design epigenetic regulation gain of function in vivo innovation loss of function mechanical load mortality mouse model muscle form muscle hypertrophy novel novel strategies permissiveness prevent promoter rRNA Genes response sarcopenia stoichiometry therapy development transcription factor transcription factor UBF transcription factor USF translational framework

项目摘要

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.

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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chemotherapy agents reduce protein synthesis and ribosomal capacity in myotubes independent of oxidative stress.

化疗药物会减少肌管中的蛋白质合成和核糖体容量，与氧化应激无关。

DOI：
10.1152/ajpcell.00116.2021
发表时间：
2021
期刊：
American journal of physiology. Cell physiology
影响因子：
0
作者：
Guo,Bin;Bennet,Devasier;Belcher,DanielJ;Kim,Hyo-Gun;Nader,GustavoA
通讯作者：
Nader,GustavoA

Reduced rDNA transcription diminishes skeletal muscle ribosomal capacity and protein synthesis in cancer cachexia.

降低的rDNA转录减少了癌症恶病质中骨骼肌核糖体能力和蛋白质合成。

DOI：
10.1096/fj.202002257r
发表时间：
2021-03
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Kim HG;Huot JR;Pin F;Guo B;Bonetto A;Nader GA
通讯作者：
Nader GA