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功能至关重要，并且在胎儿、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会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。该项目重点关注一种新型的终生肌肉健康候选调节剂。我们广泛的初步数据表明，小循环激素生长分化因子 11（GDF11，也称为骨形态发生蛋白 11 或 BMP11）在调节骨骼肌纤维的稳态重塑和肌肉干细胞（也称为卫星细胞）在生命特定阶段的再生活性方面发挥着深远的作用。特别是，对 GDF11 敲除小鼠的分析表明，该因子在中轴骨骼、内分泌和神经系统的正常发育中发挥着重要作用。尽管 GDF11 蛋白在产后组织中的作用最近才开始被探索，但 GDF11 蛋白在新生儿和年轻成年动物中以高水平循环，但随着年龄的增长而急剧下降，并与骨骼肌、心脏和神经组织中多种与年龄相关的病理的出现相一致。令人兴奋的是，我们发表和提交的手稿中的新数据表明，提高老年小鼠循环 GDF11 的水平可以显着逆转与年龄相关的病理，包括逆转心脏肥大、恢复卫星细胞数量和恢复肌肉再生潜力。在这个项目中，我们将通过以下方式回答对于了解这种新激素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) 定义整个生命周期中循环 GDF11 的细胞来源，并阐明其年龄依赖性衰退的基础，(2) 评估在生命的不同阶段去除 GDF11 对发育和稳态的影响，以及 (3) 评估人体组织和血清中 GDF11 丰度和功能的年龄调节变化。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候选疗法，用于逆转与年龄相关的骨骼肌功能障碍。