Restoring the regenerative capacity of the aged muscle

恢复老化肌肉的再生能力

• 批准号: 10241389
• 负责人: Stelios Theoharis Andreadis
• 金额: $ 39.98万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10241389
• 关键词: 3-Dimensional; Adult; Affect; Aging; Animal Model; Animals; Arteries; Biochemical Pathway; Biological Assay; Biomedical Engineering; Cell Aging; Cell Therapy; Cell model; Cell physiology; Cells; Collagen Type III; DNA Damage; Data; Development; Disease; Elastin; Elderly; Embryo; Engineering; Extracellular Matrix; Generations; Genes; Goals; Impairment; In Vitro; Laboratories; Measures; Mediating; Medical; Mesenchymal Stem Cells; Metabolic; Metabolism; Modeling; Molecular; Morbidity - disease rate; Muscle; Muscle Fibers; Muscle function; Myoblasts; Natural regeneration; Organ; Patients; Phenotype; Physiology; Premature aging syndrome; Progeria; Quality of life; Regenerative Medicine; Regenerative capacity; Reporting; Research; Resources; Risk; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal Myoblasts; Skin; Smooth Muscle Myocytes; System; Therapeutic; Time; Tissue Engineering; Tissues; Work; age effect; age related; aged; aging population; anti aging; cell age; cell injury; design; disability; druggable target; extracellular; follow-up; frailty; functional restoration; high risk; improved; in vivo; inducible gene expression; innovation; mechanical properties; mortality; mouse model; muscle aging; muscle form; muscle regeneration; new therapeutic target; novel; older patient; pluripotency; programs; regeneration potential; regenerative; response to injury; sarcopenia; senescence; skeletal muscle metabolism; small molecule; stem cells; success; therapy development; tool; transcription factor; transcriptome; transcriptome sequencing

ABSTRACT Age-related loss in muscle mass, sarcopenia, is a major medical problem facing the elderly and correlates with loss of metabolic function, disabilities, morbidity, and mortality. In addition, prolonged culture times are required to obtain the large numbers of cells necessary for regenerative medicine. As a result, the quality of the cells that are used to engineer tissues for cell therapies may be compromised by replicative senescence. In the past few years, our laboratory discovered that expression of a pluripotency-associated embryonic transcription factor, NANOG, could reverse senescence and completely restore the differentiation potential of senescent mesenchymal stem cells (MSC) and cells from progeria (accelerated aging disease) patients into functional smooth muscle cells. We also discovered that NANOG could reverse the impaired ability of senescent stem cells to produce collagen type III and elastin, which are severely affected by aging and affect the mechanical properties of tissues such as skin, arteries and skeletal muscle. Most recently we discovered that NANOG reversed the hallmarks of cellular senescence and restored the metabolic program of senescent skeletal myoblasts, ultimately restoring their ability form contractile myotubes and regenerate in response to injury. In this proposal we seek to better understand the mechanisms that mediate the effect of NANOG in vitro and in vivo through the following aims. In Aim 1, we will examine the effects of NANOG on myoblast senescence in traditional cultures as well as using bioengineered 3D skeletal muscle tissues. NANOG is expressed after cells reach senescence, thereby enabling us to measure the reversal of the aging phenotype using a plethora of cellular, molecular and functional assays. In Aim 2, we will study the effects of NANOG on restoring the metabolic function of aged myoblasts. We propose to study in detail the NANOG-induced metabolic reprogramming of aged cells and investigate potential signaling pathways that may mediate these effects. Finally, in Aim 3 we will develop a very innovative mouse model to investigate the effects of NANOG on animal physiology, skeletal muscle metabolism and regeneration. Impact: This is a very innovative proposal that seeks to investigate the potential of an embryonic transcription factor to ameliorate the effects of aging and enhance the regenerative ability of aged skeletal muscle (SkM). Understanding the mechanism(s) that mediate the effects of NANOG on metabolic reprogramming of aged SkM may enable identification of novel druggable targets and design of innovative strategies to restore the function of aged tissues. Given the surge in the aging population in the US and the world, the debilitating effects of aging on skeletal muscle and the resulting frailty condition affecting the elderly, successful attainment of this work may have significant impact in regenerative medicine and the quality of life of elderly patients.

抽象的 与年龄相关的肌肉质量损失，即肌肉减少症，是老年人面临的一个主要医学问题，并与 代谢功能丧失、残疾、发病率和死亡率。此外，还需要延长培养时间 获得再生医学所需的大量细胞。因此，细胞的质量 用于细胞治疗的组织工程可能会受到复制衰老的影响。 在过去的几年里，我们实验室发现了一种与多能性相关的胚胎的表达 转录因子NANOG可以逆转衰老并完全恢复细胞的分化潜能 衰老间充质干细胞 (MSC) 和来自早衰症（加速衰老疾病）患者的细胞 功能性平滑肌细胞。我们还发现NANOG可以逆转衰老的能力受损 干细胞产生III型胶原蛋白和弹性蛋白，它们受到衰老的严重影响并影响机械性能 皮肤、动脉和骨骼肌等组织的特性。最近我们发现 NANOG 逆转细胞衰老的标志并恢复衰老骨骼的代谢程序 成肌细胞，最终恢复其形成收缩肌管的能力并响应于再生 受伤。 在本提案中，我们寻求更好地了解介导 NANOG 体外作用的机制，以及 体内通过以下目标。在目标 1 中，我们将研究 NANOG 对成肌细胞衰老的影响 传统文化以及使用生物工程 3D 骨骼肌组织。 NANOG 在细胞后表达 达到衰老，从而使我们能够使用大量的方法来测量衰老表型的逆转 细胞、分子和功能测定。在目标 2 中，我们将研究 NANOG 对恢复代谢的影响 老化成肌细胞的功能。我们建议详细研究 NANOG 诱导的代谢重编程 老化细胞并研究可能介导这些效应的潜在信号通路。最后，在目标 3 中，我们将 开发一种非常创新的小鼠模型来研究 NANOG 对动物生理、骨骼的影响 肌肉代谢和再生。 影响：这是一个非常创新的提案，旨在研究胚胎的潜力 转录因子可改善衰老的影响并增强衰老骨骼肌的再生能力 （SkM）。了解 NANOG 对代谢重编程的影响机制 老化的 SkM 可能能够识别新的药物靶点并设计创新策略来恢复 老化组织的功能。鉴于美国和世界人口老龄化的激增， 衰老对骨骼肌的影响以及由此产生的虚弱状况影响老年人，成功的成就 这项工作可能会对再生医学和老年患者的生活质量产生重大影响。