Improving Aged Neuromuscular Health and Function

改善老年神经肌肉健康和功能

基本信息

批准号：
10444829
负责人：
Mitra Lavasani
金额：
$ 47.11万
依托单位：
REHABILITATION INSTITUTE OF CHICAGO D/B/A SHIRLEY RYAN ABILITYLAB
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444829
关键词：
Activities of Daily Living Adult Aging Anatomy Animals Antibodies Area Biological Brain Cell Therapy Cell Transplantation Cells Cessation of life Chronic Clinical Critical Pathways Data Defect Deterioration Disease Dissection Elderly Electron Microscopy Endocrine Environment Exercise Fiber Fibrosis Functional disorder Gait Growth Factor Health Histology Impairment Intervention Knowledge Longevity Mammals Measurement Mediating Methods Molecular Motor Multipotent Stem Cells Mus Muscle Muscle Fatigue Natural regeneration Nerve Degeneration Nerve Regeneration Nerve Tissue Neural Conduction Neuromuscular conditions Parabiosis Pathology Pathway interactions Peripheral Nerves Physiological Process Progeria Proteins Proteomics Publishing Quality of life Recovery of Function Regenerative capacity Rejuvenation Role Serum Signal Pathway Skeletal Muscle Specificity Spectrum Analysis Stem cell transplant Stimulus Structure System Techniques Testing Therapeutic Therapeutic Effect Therapeutic Uses Time Tissues Transplantation Weight age related aged anti aging base chemokine circulating biomarkers clinical translation clinically relevant cytokine differential expression effective therapy exercise capacity experimental study fall injury fall risk functional improvement high risk improved improved functioning light microscopy mouse model multipotent cell muscle aging muscle form muscle regeneration muscle strength myelination neovascularization neuromuscular neuromuscular function new therapeutic target novel novel strategies novel therapeutics paracrine peripheral nerve regeneration phosphoproteomics predictive marker response restoration sarcopenia sciatic nerve skeletal muscle wasting stem stem cell population stem cell therapy stem cells tandem mass spectrometry therapeutic target tissue regeneration

项目摘要

Project Summary Loss of neuromuscular function and regenerative capacity is a hallmark of aging; however, the cause of this age- related decline and the molecular pathways underlying this process remain unknown and no clinical intervention successfully arrests age-related neuromuscular dysfunction. The long-term objective of this proposal is to develop an effective stem cell-mediated therapy to ameliorate age-related deterioration of neuromuscular function. Our previously published findings show that transplantation of our unique adult multipotent muscle-derived stem/progenitor cells (MDSPCs) from young mice promotes functional peripheral nerve regeneration in mice with a sciatic nerve defect, delays the onset of aging-related diseases, and triples the lifespan in mouse models of progeria. In addition, induced neovascularization in the muscles and brain—where no transplanted cells were detected—strongly suggests a therapeutic paracrine/endocrine mechanism. Most importantly, our recent preliminary results indicate that systemic transplantation of young MDSPCs into naturally aged mice restores peripheral nerve histology and myelination, increases skeletal muscle weight and fiber cross-sectional area, decreases muscle fibrosis, and improves functional mobility and gait. These novel findings strongly suggest that young MDSPCs can modulate the systemic environment of aged animals through secreted rejuvenating factors that activate or inhibit key molecular signaling pathways critical for tissue regeneration. Thus, we hypothesize that young stem cells—or the therapeutic factors they secrete—can be used to treat chronic aging-related neuromuscular impairments. In Aim 1, we will determine to what extent systemic treatment with young MDSPCs can rejuvenate neuromuscular tissue structure and motor function in naturally aged mice by using clinically relevant techniques such as real-time Resonant Reflection Spectroscopy (RRS), muscle contractile force measurement, nerve conduction testing, and longitudinal motor function testing of mobility, gait, and muscle fatigue. In Aim 2, we will identify the underlying molecular mechanism(s) of neuromuscular functional improvements resulting from transplantation of young MDSPCs, using multiplexing-tandem mass spectrometry and [phosphoproteomics], as well as identify proteins circulating in the blood serum involved in this systemic rejuvenation. Aim 3 will uncover key factors secreted by young MDSPCs that drive neuromuscular tissue rejuvenation and improve function using a quantitative multiplex antibody array system. Together, these aims will uncover the mechanisms of young MDSPC-mediated neuromuscular tissue rejuvenation and functional improvements, identify circulating biomarkers that predict neuromuscular health in aged mammals, and facilitate the discovery of novel stem cell–based therapeutic targets for clinical use.

项目摘要神经肌肉功能和再生能力的丧失是衰老的标志。但是，这个年龄的原因 - 相关下降和此过程的基本途径仍然未知，没有临床干预成功阻止了与年龄相关的神经肌肉功能障碍。该建议的长期目标是开发有效的干细胞介导的疗法以改善与年龄相关的神经肌肉功能的定义。我们先前发表的发现表明，移植我们独特的成人多能肌衍生的茎/祖细胞（MDSPC）的年轻小鼠促进坐骨神经缺陷的小鼠功能性周围神经再生，延迟了与衰老有关的发作疾病和呈启动小鼠模型中的寿命三倍。另外，在肌肉和大脑（未检测到移植细胞）严重地提出了一种治疗旁分泌/内分泌机制。最重要的是，我们最近的初步结果表明系统性将年轻的MDSPC移植到天然老化的小鼠中，恢复周围神经组织学和髓鞘形成，增加骨骼肌肉重量和纤维横截面区域，减少肌肉纤维化并改善功能流动性和步态。这些新颖的发现强烈表明，年轻的MDSPC可以调节通过分泌的复兴因子激活或抑制关键分子的分泌复兴因子的衰老动物的全身环境信号通路对于组织再生至关重要。那就是我们假设年轻的干细胞 - 或他们秘密的治疗因素 - 可用于治疗慢性衰老相关的神经肌肉障碍。在AIM 1中，我们将确定对年轻MDSPC的系统治疗在多大程度上可以恢复活力通过使用临床相关技术，天然老化小鼠的神经肌肉组织结构和运动功能例如实时谐振反射光谱（RRS），肌肉收缩力测量，神经传导测试以及迁移，步态和肌肉疲劳的纵向运动功能测试。在AIM 2中，我们将确定由神经肌肉功能改善的基本分子机制使用多路复用串联质谱和[磷蛋白质组学]的年轻MDSPC的移植AS 以及鉴定在这种系统性修订中涉及的血清中循环的蛋白质。 AIM 3将发现年轻的MDSPC分泌的关键因素可以驱动神经肌肉组织的复兴和改善功能定量多抗体阵列系统。总之，这些目标将发现年轻MDSPC介导的神经肌肉组织的机制恢复活力和功能改进，确定循环的生物标志物，以预测神经肌肉健康老化的哺乳动物，并促进发现新型干细胞的临床治疗靶标。