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.

项目概要神经肌肉功能和再生能力的丧失是衰老的标志。相关的衰退和该过程背后的分子途径仍然未知，也没有临床干预成功阻止与年龄相关的神经肌肉功能障碍。该提案的长期目标是开发一种有效的干细胞介导的疗法来改善我们之前发表的研究结果表明，移植会导致与年龄相关的神经肌肉功能恶化。我们独特的来自年轻小鼠的成体多能肌肉源性干细胞/祖细胞 (MDSPC) 促进坐骨神经缺陷小鼠的功能性周围神经再生，延缓衰老相关疾病的发生疾病，并使早衰小鼠模型的寿命延长三倍。此外，还诱导了新生血管形成。肌肉和大脑（没有检测到移植细胞）强烈表明有一种治疗方法最重要的是，我们最近的初步结果表明，系统性的。将年轻的 MDSPC 移植到自然衰老的小鼠体内可恢复周围神经组织学和髓鞘形成，增加骨骼肌重量和纤维横截面积，减少肌肉纤维化，并改善这些新发现强烈表明，年轻的 MDSPC 可以调节功能移动和步态。通过分泌的激活或抑制关键分子的恢复活力因子来调节衰老动物的全身环境对组织再生至关重要的信号通路因此，我们采用了年轻的干细胞。它们分泌的治疗因子可用于治疗与衰老相关的慢性神经肌肉损伤。在目标 1 中，我们将确定年轻 MDSPC 的系统治疗可以在多大程度上恢复活力使用临床相关技术研究自然衰老小鼠的神经肌肉组织结构和运动功能例如实时共振反射光谱（RRS）、肌肉收缩力测量、神经在目标 2 中，我们将进行传导测试以及移动性、步态和肌肉疲劳的纵向运动功能测试。确定神经肌肉功能改善的潜在分子机制使用多重串联质谱和[磷酸蛋白质组学]移植年轻的 MDSPC，如目标 3 将揭示血清中循环的蛋白质与系统性复兴的相关性。年轻 MDSPC 分泌的关键因子可驱动神经肌肉组织再生并改善功能定量多重抗体阵列系统。这些目标共同将揭示年轻 MDSPC 介导的神经肌肉组织的机制恢复活力和功能改善，识别预测神经肌肉健康的循环生物标志物老年哺乳动物，并促进发现基于干细胞的新型临床治疗靶点。