Improving Aged Neuromuscular Health and Function

改善老年神经肌肉健康和功能

• 批准号: 10631195
• 负责人: Mitra Lavasani
• 金额: $ 47.2万
• 依托单位: REHABILITATION INSTITUTE OF CHICAGO D/B/A SHIRLEY RYAN ABILITYLAB
• 依托单位国家: 美国
• 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/10631195
• 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; 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; 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 cell population; stem cell therapy; stem cells; tandem mass spectrometry; therapeutic target; tissue regeneration

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;然而，这个年龄的原因- 相关的下降和该过程的分子途径仍然未知，也没有临床干预 成功阻止了年龄相关的神经肌肉功能障碍 这项提案的长期目标是开发一种有效的干细胞介导的治疗方法，以改善 与年龄相关的神经肌肉功能衰退。我们先前发表的研究结果表明， 我们独特的来自年轻小鼠的成体多能肌源性干/祖细胞（MDSPCs） 功能性周围神经再生在小鼠坐骨神经缺损，延缓衰老相关的发病 疾病，并在小鼠模型的早衰症寿命的三倍。此外，诱导的新生血管在 肌肉和大脑-没有检测到移植细胞-强烈表明治疗 旁分泌/内分泌机制。最重要的是，我们最近的初步结果表明， 将年轻的MDSPC移植到自然老化的小鼠中恢复外周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， 功能性活动和步态。这些新的发现有力地表明，年轻的MDSPC可以调节 通过分泌激活或抑制关键分子的返老还童因子， 对组织再生至关重要的信号通路。因此，我们假设年轻的干细胞--或 它们分泌的治疗因子可用于治疗慢性衰老相关的神经肌肉损伤。 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 自然衰老小鼠神经肌肉组织结构和运动功能的研究 例如实时共振反射光谱（RRS）、肌肉收缩力测量、神经 传导测试和纵向运动功能测试的移动性、步态和肌肉疲劳。在目标2中，我们将 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，作为 以及鉴定血清中循环的蛋白质，这些蛋白质参与了全身性的年轻化。目标3将揭示 年轻的MDSPC分泌的关键因子，驱动神经肌肉组织再生和改善功能， 一种定量多重抗体阵列系统。 总之，这些目标将揭示年轻的MDSPC介导的神经肌肉组织的机制， 年轻化和功能改善，确定预测神经肌肉健康的循环生物标志物， 老年哺乳动物，并有助于发现新的基于干细胞的治疗靶点用于临床应用。

项目成果

Sex-specific preservation of neuromuscular function and metabolism following systemic transplantation of multipotent adult stem cells in a murine model of progeria.

• DOI: 10.1007/s11357-023-00892-5
• 发表时间: 2024-02
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Thompson, Seth D. D.;Barrett, Kelsey L. L.;Rugel, Chelsea L. L.;Redmond, Robin;Rudofski, Alexia;Kurian, Jacob;Curtin, Jodi L. L.;Dayanidhi, Sudarshan;Lavasani, Mitra
• 通讯作者: Lavasani, Mitra