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

• 批准号: 9045972
• 负责人: AMY JO WAGERS
• 金额: $ 33.8万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045972
• 关键词: Adolescent; Adult; Age; Aging; Animals; Biology of Aging; Blood; Caloric Restriction; Cardiac; Cell Count; Cells; Data; Detection; Development; Developmental Biology; Differentiation and Growth; Elderly; Embryonic Development; Employee Strikes; Endocrine system; Excision; Exhibits; Exposure to; Frequencies; Functional disorder; Genetic Models; Growth; Health; Heart; Heart Hypertrophy; Homeostasis; Hormones; Human; In Vitro; Individual; Injection of therapeutic agent; Knock-in Mouse; Knockout Mice; Laboratories; Life; Longevity; Maintenance; Manuscripts; Mediating; Mus; Muscle; Muscle Development; Muscle Fibers; Muscle function; Muscle satellite cell; Natural regeneration; Neonatal; Nervous system structure; Organ; Parabiosis; Pathology; Patients; Peripheral; Phenotype; Physical Function; Physiology; Play; Population; Process; Production; Proteins; Publishing; Quality of life; Recombinant Proteins; Recovery; Regulation; Reporter; Role; Serum; Skeletal Muscle; Somatotropin; Source; Staging; System; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Western Blotting; Work; Youth; age related; aged; base; bone morphogenic protein; cohort; experience; fetal; human tissue; improved; in vivo; injured; insight; mRNA Expression; mature animal; middle age; mortality; mouse Gdf11 protein; muscle aging; muscle form; muscle strength; myogenesis; novel; novel strategies; premature; prototype; regenerative; relating to nervous system; repaired; research study; restoration; satellite cell; skeletal; small molecule; young adult

DESCRIPTION (provided by applicant): Healthy skeletal muscle is essential to sustain normal physical function, and 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 leads 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 focuses on a novel candidate regulator of muscle health throughout life. Our extensive preliminary data indicate that the small circulating hormone Growth Differentiation Factor 11 (GDF11, also known as Bone Morphogenic Protein 11, or BMP11) plays a profound role in modulating the homeostatic remodeling of skeletal muscle fibers and the regenerative activity of muscle stem cells (also known as satellite cells) at particular stages of life. In particular, analysis of GDF11 knockout mice indicates an essential role for this factor in normal development of the axial skeletal and endocrine and nervous system. Although its role in post-natal tissues has only recently begun to be explored, GDF11 protein circulates at high levels in neonatal and young adult animals, but declines dramatically with advancing age and in concert with the emergence of multiple age-associated pathologies in skeletal muscle, as well as cardiac and neural tissue. Excitingly, new data from our published and submitted manuscripts indicate that raising the levels of circulating GDF11 in aged mice can produce a striking reversal of age-related pathologies, including reversal of cardiac hypertrophy, recovery of satellite cell numbers and restoration of muscle regenerative potential. In this project, we will answer questions crucial to understanding the regulation and activity of this new hormone and its potential for regulating developmental and aging phenotypes in mice and humans by: (1) defining the cellular source(s) of circulating GDF11 throughout life and clarifying the basis for its age-dependent decline, (2) evaluating the impact on development and homeostasis of removal of GDF11 at discrete stages of life, and (3) assessing age-regulated changes in GDF11 abundance and function in human tissue and sera. Together, these studies will provide critical insights into muscle developmental biology and aging and may validate a promising 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机能至关重要，并且在胎儿，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，肌肉稳态受损和肌肉再生潜力降低会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。该项目着重于一生中新型肌肉健康的候选监管者。我们广泛的初步数据表明，小循环激素生长分化因子11（GDF11，也称为骨形态形态蛋白11或BMP11）在调节骨骼肌纤维的稳态重塑中起着重要作用，在特定阶段的肌肉干细胞（也称为肌肉干细胞）（也称为肌肉干细胞的再生活性）。特别是，对GDF11敲除小鼠的分析表明，该因素在轴向骨骼和内分泌系统正常发育中的重要作用。尽管其在产后组织中的作用最近才开始探索，但GDF11蛋白在新生儿和成年动物的高水平循环中循环，但随着年龄的增长，与骨骼肌以及心脏和神经组织的多个年龄相关病理的出现急剧下降。令人兴奋的是，来自我们已发表和提交的手稿的新数据表明，老年小鼠中循环GDF11的水平可以产生与年龄相关的病理学的惊人逆转，包括心脏肥大的逆转，卫星细胞的恢复和肌肉再生潜力的恢复。在该项目中，我们将回答有关理解这种新激素的调节和活动至关重要的问题，及其在小鼠和人类中调节发育和衰老表型的潜力：（1）定义循环GDF11的细胞来源（S）在整个生命中的循环源，并阐明其与年龄相关的衰落的基础，以评估其依赖于发展的发展，（2）评估其持续性的影响，（2）裁员的持续性，GAD的持续效果是裁定的，GD F. RESS of dist of the Idal of Servue of the Idal of the gy of the p.11 （3）评估人体组织和血清中GDF11丰度和功能的年龄调节变化。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，并可以验证有前途的候选治疗方法，以逆转与年龄相关的骨骼肌功能障碍。