Regulation and function of Growth Differentiation Factor 11 during development and aging

生长分化因子11在发育和衰老过程中的调节和功能

基本信息

批准号：
9886169
负责人：
AMY JO WAGERS
金额：
$ 52.77万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886169
关键词：
Adolescent Adult Age Age Factors Aging Animals Biology of Aging Blood Body Composition Brain Caloric Restriction Cardiac Cell Count Cells Data Detection Development Developmental Biology Elderly Embryonic Development Enzyme-Linked Immunosorbent Assay Excision Exhibits Exposure to Frequencies Functional disorder GDF11 gene Genetic Models Growth Heart Histologic Homeostasis Hormones Human Immunoassay Impairment Individual Injury Knock-in Laboratories Lead Life Longevity Maintenance Manuscripts Mediating Messenger RNA Morbidity - disease rate Mus Muscle Muscle Development Muscle Fibers Muscle function Muscle satellite cell Muscular Atrophy Muscular Dystrophies Myopathy Natural regeneration Neonatal Organ Parabiosis Pathology Pathway interactions Patients Performance Peripheral Phenotype Physical Function Physiology Play Population Process Production Proteins Publishing Quality of life Recombinant Proteins Recovery Regulation Reporter Rest Role Serum Signal Transduction Skeletal Muscle Source Supplementation System Testing Therapeutic Tissues Transgenic Organisms Work Youth age related aged bone morphogenic protein cell type cohort experience experimental study fetal improved in vivo injured insight loss of function mRNA Expression mature animal middle age mortality muscle aging muscle form muscle strength myogenesis novel novel strategies pleiotropism premature protective factors public health relevance regenerative repaired restoration sarcopenia satellite cell small molecule therapeutic candidate young adult

项目摘要

DESCRIPTION (provided by applicant): Healthy skeletal muscle is essential to sustain normal physical function, and muscle undergoes multiple developmental and functional transitions during fetal, neonatal and adult life. In the latest stages of life, impaired muscle homeostasis and reduced muscle regenerative potential lead to progressive loss of muscle mass and strength. Importantly, reduced muscle function in elderly individuals is one of the strongest predictors of imminent mortality, suggesting that improved understanding of the fundamental mechanisms underlying muscle aging and the development of novel strategies to intervene in this process, would have tremendous impact on lifespan and quality of life of the growing population of aged individuals experiencing degenerative muscle decline. This project is aimed at increasing our understanding of skeletal muscle function throughout life by focusing on a novel circulating hormone called Growth Differentiation Factor 11 (GDF11, also known as Bone Morphogenic Protein 11, or BMP11). Extensive published and preliminary data indicate that GDF11 plays a key role in modulating the homeostatic remodeling of skeletal muscle fibers and the regenerative activity of muscle stem cells (satellite cells) at particular stages of life. GDF1 protein circulates at high levels in neonatal and young adult animals (including humans), but declines dramatically with advancing age and in concert with the emergence of multiple age-associated pathologies in muscle and other tissues. Data from our recently published manuscripts indicate that raising the levels of circulating GDF11 in aged mice can reverse certain age-related pathologies, including recovery of satellite cell numbers in resting muscle and restoration of muscle regenerative potential after mild muscle injury. However, overproduction of this protein in younger mice subjected to severe muscle damage may have a detrimental effect. In this project, we will answer questions crucial to understanding the regulation and activity of this new candidate rejuvenating factor for aged muscle, and its potential for regulating developmental and aging phenotypes in mice and humans by: (1) defining the cellular source(s) of GDF11 throughout life and clarifying the basis for the age-dependent decline of this hormone and its potential age- and injury-dependent effects on muscle repair, (2) evaluating the impact on development and homeostasis of removal of GDF11 at discrete stages of life or in discrete GDF11- producer cells, and (3) assessing age-regulated changes in GDF11 abundance and function in human sera and correlating these with muscle performance, body composition and overall physical function in individuals with or without mobility limitations. Together, these studies will provide critical insights into muscle developmental biology and aging and may validate a promising new candidate therapeutic for the reversal of age-related skeletal muscle dysfunction.

描述（由适用提供）：健康的骨骼肌对于维持正常的身体机能至关重要，肌肉在胎儿，新生儿和成人生活期间经历多次发育和功能过渡。在生活的最新阶段，肌肉体内稳态受损和肌肉再生潜力降低导致肌肉质量和力量的逐渐丧失。重要的是，老年人的肌肉功能降低是即将死亡的最强预测指标之一，这表明对肌肉衰老的基本机制的理解以及介入这一过程的新型策略的发展将对寿命和衰老的生活质量产生巨大影响。该项目旨在通过专注于一种称为生长分化因子11（GDF11，也称为骨形态形态蛋白11或BMP11）的新型循环马体来增强我们对骨骼肌功能的理解。广泛的发表和初步数据表明，GDF11在调节骨骼肌纤维的体内稳态重塑和肌肉干细胞（卫星细胞）的再生活性中起着关键作用。 GDF1蛋白在新生儿和成年动物（包括人类）中高水平的蛋白质圈，但随着年龄的增长和与多种年龄相关的肌肉和其他时代的多种相关病理的出现而急剧下降。来自我们最近发表的手稿的数据表明，在老年小鼠中提高循环GDF11的水平可以逆转某些与年龄相关的病理，包括在轻度肌肉损伤后恢复静止肌肉和肌肉再生潜力的卫星细胞数量。但是，在遭受严重肌肉损伤的年轻小鼠中该蛋白质过量产生可能会产生有害作用。在该项目中，我们将回答有关了解这种新候选者对衰老肌肉的调节和活动至关重要的问题，及其在小鼠和人类中的调节性发育和衰老表型的潜力，通过：（1）定义GDF11的细胞来源，并阐明了这种依赖于年龄的基础，并阐明了群体依赖于年龄的基础，并依赖于群体依赖于年龄的基础，并依赖于群体依赖的群体，并且依赖于群体依赖于年龄范围，并且依赖于年龄的降低，并且依赖于年龄的降低，并且依赖于年龄的降低，并且依赖于年龄的降低，并且依赖于年龄的降低，并且降低了依赖于年龄的降低。在生命的离散阶段或离散的GDF11-生产细胞中删除GDF11的发展和稳态的影响，以及（3）评估GDF11抽象的年龄变化和人类血清中的功能，并将其与具有或没有移动性限制的个体的肌肉表现，身体组成和整体官能相关。这些研究将共同提供对肌肉发育生物学和衰老的关键见解，并可能验证有希望的新候选疗法，以反转与年龄相关的骨骼肌功能障碍。