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控和功能

• 批准号: 9392347
• 负责人: AMY JO WAGERS
• 金额: $ 11.58万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9392347
• 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; public health relevance; regenerative; repaired; restoration; sarcopenia; satellite cell; small molecule; therapeutic candidate; young adult

 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（由申请人提供）：健康的骨骼肌对于维持正常的身体功能至关重要，并且肌肉在胎儿、新生儿和成人生命期间经历多种发育和功能转变。在生命的最后阶段，肌肉稳态受损和肌肉再生潜力降低导致肌肉质量和力量逐渐丧失。重要的是，老年人肌肉功能下降是即将死亡的最强预测因素之一，这表明提高对肌肉衰老基本机制的了解并开发干预这一过程的新策略，将对不断增长的经历退行性肌肉衰退的老年人群的寿命和生活质量产生巨大影响。该项目旨在通过关注一种名为生长分化因子 11（GDF11，也称为骨形态发生蛋白 11 或 BMP11）的新型循环激素，增进我们对整个生命过程中骨骼肌功能的了解。大量已发表的初步数据表明，GDF11 在调节骨骼肌纤维的稳态重塑和生命特定阶段肌肉干细胞（卫星细胞）的再生活性方面发挥着关键作用。 GDF1 蛋白在新生儿和年轻成年动物（包括人类）中以高水平循环，但随着年龄的增长以及肌肉和其他组织中多种与年龄相关的病理的出现而急剧下降。我们最近发表的手稿中的数据表明，提高老年小鼠循环 GDF11 的水平可以逆转某些与年龄相关的病理，包括恢复静息肌肉中的卫星细胞数量以及恢复轻度肌肉损伤后的肌肉再生潜力。然而，在遭受严重肌肉损伤的年轻小鼠中，这种蛋白质的过量产生可能会产生有害影响。在这个项目中，我们将通过以下方式回答对于了解这种新的候选衰老肌肉恢复因子的调节和活性及其调节小鼠和人类发育和衰老表型的潜力至关重要的问题：(1) 确定整个生命过程中 GDF11 的细胞来源，并阐明这种激素随年龄而下降的基础及其对肌肉修复的潜在年龄和损伤依赖性影响，(2) 评估 在生命的不同阶段或在离散的 GDF11 生产细胞中去除 GDF11 对发育和稳态的影响，以及 (3) 评估人类血清中 GDF11 丰度和功能的年龄调节变化，并将这些变化与有或没有活动限制的个体的肌肉性能、身体成分和整体身体功能相关联。总之，这些研究将为肌肉发育生物学和衰老提供重要见解，并可能验证一种有前途的新候选疗法，用于逆转与年龄相关的骨骼肌功能障碍。