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Transcriptional Control of Skeletal Muscle Atrophy

骨骼肌萎缩的转录控制

基本信息

批准号：
10343741
负责人：
Grant D Barish
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
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：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343741
关键词：
Affect Age Aging American Atrophic Autophagocytosis BCL6 gene Binding Sites Biochemical Bioinformatics Biological Assay Body Composition Caloric Restriction Cessation of life ChIP-seq Complex Data Deuterium Diabetes Mellitus Disease Enhancers Eukaryotic Initiation Factor-4E Exercise FRAP1 gene Fasting General Population Genes Genetic Engineering Genetic Transcription Hand Strength Health Care Costs Heart failure Histones Homeostasis Injury Isometric Exercise Kidney Failure Kinetics Knockout Mice Label Link Lysine Malignant Neoplasms Malnutrition Measures Medical Metabolism Molecular Morbidity - disease rate Mus Muscle Muscle Cells Muscle Proteins Muscular Atrophy Myosin ATPase Nucleic Acid Regulatory Sequences Pathway interactions Performance Pharmaceutical Preparations Physiological Play Polyribosomes Prevalence Prevention Protein Biosynthesis Protein Isoforms Proteins Puromycin Regulation Regulator Genes Risk Role Signal Transduction Skeletal Muscle Somatotropin Source Stains Switch Genes Testing Therapeutic Tissues Transcription Repressor Transcriptional Regulation Transgenic Organisms Translation Initiation Translations Tyrosine Veterans acute infection base chronic infection disability epigenomics gain of function gene regulatory network genome-wide histone modification in vivo inhibitor insight military service mortality muscle form nutrition overexpression prevent promoter protein degradation proteostasis response sarcopenia skeletal muscle wasting transcriptome sequencing

项目摘要

Skeletal muscle atrophy results from insufficient nutrition, aging, certain medications, and a wide range of medical illnesses including cancer, diabetes mellitus, heart or renal failure, and acute or chronic infections. It is linked to increased disability, morbidity, as well as mortality, afflicts millions of Americans, and accounts for tens of billions of dollars in annual healthcare costs. Moreover, veterans are projected to have an increased prevalence of muscle atrophy compared to the general population because of military service-related injuries and medical conditions as well as their older age. Yet, there are no currently approved medical therapies for muscle atrophy, and the molecular determinants that control muscle mass remain incompletely defined. Using conditional genetic engineering, we have identified a surprising new role for the B cell lymphoma 6 (BCL6) transcriptional repressor to maintain muscle mass. Herein, we propose to comprehensively dissect the function of BCL6 in muscle and its epigenomic regulation. In Aim 1, we will test the impact of BCL6 on muscle protein synthesis and degradation, muscle mass, myofiber specification and metabolism, strength, and whole body energy homeostasis. In Aim 2, we will define the genome-wide gene regulatory network for BCL6 and its epigenomic, molecular, and biochemical mechanisms for controlling proteostasis. Together, these studies will reveal new molecular insights and a potential therapeutic pathway to reduce the burden of skeletal muscle loss.

骨骼肌萎缩是由于营养不足，衰老，某些药物和广泛的医学疾病，包括癌症、糖尿病、心脏或肾衰竭以及急性或慢性感染。是与增加的残疾，发病率以及死亡率有关，折磨着数百万美国人，占数千人的比例。每年数十亿美元的医疗费用。此外，退伍军人预计将增加与一般人群相比，由于与军事服务有关的伤害而导致的肌肉萎缩的患病率以及他们的年龄。然而，目前还没有批准的药物疗法肌肉萎缩和控制肌肉质量的分子决定因素仍然不完全确定。使用条件遗传工程，我们已经确定了一个令人惊讶的新作用的B细胞淋巴瘤6（BCL 6）转录抑制子来维持肌肉质量。在此，我们建议全面剖析 BCL 6在肌肉中的表达及其表观基因调控。在目标1中，我们将测试BCL 6对肌肉蛋白质的影响合成和降解、肌肉质量、肌纤维规格和代谢、力量和全身能量平衡在目标2中，我们将定义BCL6的全基因组基因调控网络及其表达。表观基因组、分子和生物化学机制来控制蛋白质稳态。这些研究将揭示了新的分子见解和潜在的治疗途径，以减少骨骼肌损失的负担。