Development of a Cell-Based Therapy to Improve Recovery Following Immobilization

开发基于细胞的疗法以改善固定后的恢复

基本信息

项目摘要

ABSTRACT Long-term immobilization or extended bed rest following severe injury or disease can initiate rapid and significant loss of skeletal muscle mass and function. Recovery may be slow and long-term disability is a potential outcome, particularly in older adults. Physical rehabilitation is commonly prescribed for individuals subjected to long-term bed rest, yet mobility may be severely compromised in older adults and intensity of movement may not be sufficient to facilitate full recovery. Thus, novel regenerative therapies are necessary to maximize positive outcomes associated with rehabilitation to prevent or treat long-term disability associated with immobilization in older adults. Pericytes are multipotent stem cells that reside around microvessels and capillaries and provide important structural and paracrine support necessary to regulate vessel permeability, vessel diameter and blood flow, endothelial cell proliferation, and stabilization of newly formed capillaries. Data from our laboratory demonstrate that perivascular stem and stromal cells are highly sensitive to biophysical cues in the niche, and that pericyte transplantation in combination with a physiological stimulus (exercise) can promote the release of regenerative growth and neurotrophic factors that positively influence skeletal muscle repair, growth, and strength. Thus, pericytes represent a clinically relevant cell source to expedite recovery of muscle mass and strength following a short or prolonged period of immobilization. The specific objective of this proposal is to exploit the mechanosensing properties of pericytes for the purpose of developing a new and exciting cell-based skeletal muscle rehabilitation strategy. Our central hypothesis is that there are pericyte subpopulations in skeletal muscle that are divergent in their response to a mechanical stimulus and uniquely assist with the recovery of muscle mass and strength following remobilization. Thus, this work seeks to: 1) determine the impact of mechanical strain on pericyte function, 2) determine the contribution of pericytes to skeletal muscle mass recovery following a period of immobilization in mice, and 3) develop a pericyte-derived exosome-based therapy for skeletal muscle recovery following a period of immobilization in mice. The work is highly innovative given the potential to identify a specific perivascular stem/stromal cell source with exceptional potential to recover skeletal muscle mass and function following a period of immobilization. The proposed work is significant because it is expected to create a superior pre-clinical strategy that can prevent and/or treat age-related disabilities, improving the quality of life for our growing aged population and reducing burden on the US healthcare system.
摘要 严重损伤或疾病后的长期固定或长期卧床休息可引发快速和 骨骼肌质量和功能的显著丧失。恢复可能是缓慢的,长期残疾是一个 潜在的结果,特别是在老年人。身体康复通常是为个人规定的 长期卧床休息,但老年人的活动能力可能会严重受损, 运动可能不足以促进完全恢复。因此,需要新的再生疗法, 最大限度地提高康复的积极效果,以预防或治疗与长期残疾相关的疾病。 与老年人的固定有关。周细胞是存在于微血管周围的多能干细胞, 毛细血管,并提供重要的结构和旁分泌的支持,必要的调节血管渗透性, 血管直径和血流、内皮细胞增殖和新形成的毛细血管的稳定。数据 我们实验室的研究表明,血管周围的干细胞和基质细胞对生物物理刺激高度敏感, 提示,周细胞移植与生理刺激(运动)相结合, 促进再生生长和神经营养因子的释放,积极影响骨骼肌 修复,生长,和力量。因此,周细胞代表了临床相关的细胞来源,以加快恢复。 肌肉质量和力量经过短期或长期的固定。这一具体目标 建议是利用周细胞的机械感测特性,以开发一种新的 令人兴奋的基于细胞的骨骼肌康复策略。我们的中心假设是, 骨骼肌中对机械刺激的反应不同的亚群, 独特地协助肌肉质量和力量的恢复后再动员。因此,这项工作 旨在:1)确定机械应变对周细胞功能的影响,2)确定 在小鼠中固定一段时间后,周细胞到骨骼肌质量的恢复,以及3)发展成 基于周细胞衍生的外泌体的治疗用于在一段时间的固定后的骨骼肌恢复, 小鼠这项工作是高度创新的潜力,以确定一个特定的血管周围干/基质细胞 来源具有特殊的潜力,恢复骨骼肌质量和功能后,一段时间的 固定化。拟议的工作是重要的,因为它有望创造一个上级临床前 可以预防和/或治疗与年龄有关的残疾的战略,提高我们日益增长的老年人的生活质量 减轻美国医疗系统的负担。

项目成果

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Marni D. Boppart其他文献

Marni D. Boppart的其他文献

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{{ truncateString('Marni D. Boppart', 18)}}的其他基金

Development of a Cell-Based Therapy to Improve Recovery Following Immobilization
开发基于细胞的疗法以改善固定后的恢复
  • 批准号:
    10200674
  • 财政年份:
    2018
  • 资助金额:
    $ 33.28万
  • 项目类别:
Development of a Cell-Based Therapy to Improve Recovery Following Immobilization
开发基于细胞的疗法以改善固定后的恢复
  • 批准号:
    10445294
  • 财政年份:
    2018
  • 资助金额:
    $ 33.28万
  • 项目类别:
Alpha7 Integrin-Mediated Hypertrophic Signaling and Growth in Skeletal Muscle
Alpha7 整合素介导的骨骼肌肥大信号传导和生长
  • 批准号:
    8766968
  • 财政年份:
    2014
  • 资助金额:
    $ 33.28万
  • 项目类别:

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