Restoring the regenerative capacity of the aged muscle

恢复老化肌肉的再生能力

• 批准号: 10034130
• 负责人: Stelios Theoharis Andreadis
• 金额: $ 44.08万
• 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/10034130
• 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; Gene Expression Profiling; 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; 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; metabolic profile; mortality; mouse model; muscle aging; muscle form; muscle regeneration; new therapeutic target; novel; older patient; pluripotency; programs; 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 肌肉减少症与年龄有关的肌肉质量损失是老年人面临的主要医学问题，与 代谢功能，残疾，发病率和死亡率的丧失。另外，需要延长文化时间 获得再生医学所需的大量细胞。结果，细胞的质量 用于设计细胞疗法的组织可能会因复制衰老而受到损害。 在过去的几年中，我们的实验室发现多能相关的胚胎的表达 转录因子Nanog可以逆转衰老并完全恢复分化潜力 衰老间充质干细胞（MSC）和来自后代（加速衰老疾病）患者的细胞进入 功能平滑肌细胞。我们还发现Nanog可能会扭转衰老能力受损 干细胞产生III型胶原蛋白和弹性蛋白，这些胶原蛋白受到衰老的严重影响并影响机械 皮肤，动脉和骨骼肌等组织的特性。最近我们发现了Nanog 扭转了细胞衰老的标志，并恢复了衰老骨骼的代谢程序 成肌细胞，最终恢复其能力形成收缩的肌管，并在响应 受伤。 在这项建议中，我们试图更好地了解介导纳米在体外效果和的机制 通过以下目标进行体内。在AIM 1中，我们将检查Nanog对成肌细胞衰老的影响 传统培养物以及使用生物工程的3D骨骼肌组织。 Nanog在细胞后表达 到达衰老，从而使我们能够使用大量 细胞，分子和功能测定。在AIM 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 老化的细胞并研究可能介导这些作用的潜在信号通路。最后，在目标3中，我们将 开发一个非常创新的小鼠模型来研究纳米对动物生理，骨骼的影响 肌肉代谢和再生。 影响：这是一个非常创新的建议，旨在研究胚胎的潜力 转录因子可以改善衰老的影响并增强老化骨骼肌的再生能力 （SKM）。了解介导纳米对代谢重编程的影响的机制 老化的SKM可以鉴定新的可毒靶标和创新策略的设计，以恢复 老化组织的功能。鉴于美国和世界老龄化的人口激增，使人衰弱 衰老对骨骼肌的影响以及影响老年人的脆弱状况 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。