Restoring the regenerative capacity of the aged muscle

恢复老化肌肉的再生能力

• 批准号: 10417266
• 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/10417266
• 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.

摘要