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Role of extracellular matrix in age-related declines of muscle regeneration

细胞外基质在年龄相关的肌肉再生衰退中的作用

基本信息

批准号：
10785070
负责人：
Fabrisia Ambrosio
金额：
$ 45.84万
依托单位：
SPAULDING REHABILITATION HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10785070
关键词：
3-Dimensional Achievement Address Affect Age Aging Animals Architecture Biochemical Bioenergetics Biological Models Biomechanics Biophysics Cell Lineage Cells Characteristics Collagen Collagen Fibril Cues Custom Deposition Deterioration Development Elastic Tissue Elasticity Elderly Engineering Epigenetic Process Exposure to Extracellular Matrix Fibroblasts Fibrosis Foundations Functional disorder Gene Expression Goals Impaired healing Impairment In Vitro Individual Injury Instruction Knowledge Laboratories Longevity Measures Mechanical Stimulation Mechanics Mediating Methods Methylation Modification Modulus Molecular Morphology Muscle Muscle satellite cell Natural regeneration Operative Surgical Procedures Pathogenicity Play Population Proliferating Property Proteins Recovery of Function Regenerative capacity Regenerative response Rejuvenation Repression Reserve Cell Role Signal Transduction Skeletal Muscle Skeletal muscle injury Specific qualifier value Stretching System Testing Time Tissue Engineering Tissues Trauma age effect age related age-related muscle loss aged biophysical properties cell behavior design functional decline healing histone modification impaired driving performance improved in vitro Model in vivo injury recovery insight interest mechanical load mechanical stimulus mouse model muscle aging muscle regeneration neuromuscular stimulation novel novel therapeutics osteogenic pressure promoter regeneration potential response self-renewal stem stem cell biology stem cell fate stem cell function stem cell niche stem cells superresolution imaging tissue regeneration

项目摘要

ABSTRACT Skeletal muscle trauma resulting from an injury or surgery often results in significant functional declines in older adults. These declines are at least partially attributed to failed muscle healing. Muscle regeneration is predominantly dictated by the action of muscle stem, or “satellite”, cells (MuSCs), a reserve cell population that typically demonstrates considerable dysfunction with increasing age. According to the stem cell “niche” concept, stem cell responses are largely determined by biophysical and biochemical cues that emanate from the surrounding microenvironment. Indeed, expanding recognition of the influence of the microenvironment on stem cell behavior has led to a recent surge in the development of bioinspired and engineered extracellular matrix (ECM) approaches for the treatment of skeletal muscle injuries. Still lacking, however, is an in-depth knowledge of whether and how pathogenic instructional characteristics of the native ECM disrupt MuSC function and skeletal muscle regeneration. While it is evident that MuSC activation, self-renewal, proliferation and differentiation are influenced by physical and dynamic niche interactions, a mechanistic understanding of the direct impact of age-related ECM alterations on skeletal muscle regenerative capacity is unknown. The over-arching goal of this project is to test our central hypothesis that age-related biophysical alterations in the skeletal muscle ECM promotes a fibrogenic conversion in MuSCs, ultimately driving impaired skeletal muscle regeneration. Further, we hypothesize that these pathogenic biophysical changes may be reverted, at least partially, by mechanical stimulation. To achieve this goal, we will employ an integrated approach that encompasses cutting-edge super-resolution imaging and 3-D tissue engineering methods to address two specific aims. Aim 1 studies will measure, manipulate, and mimic the biophysical properties of young and aged skeletal muscle ECM in order to dissect the effect of age-related architectural and elastic ECM modifications on MuSC fate. Aim 2 studies will identify mechanisms by which mechanical stimulation modulates biophysical properties of the aged ECM to promote MuSC myogenicity and muscle regeneration. Successful achievement of these aims will further our understanding of 1) the instructional capabilities of the native ECM on MuSC lineage specification, 2) how these instructional capabilities change over time, and 3) the molecular mechanisms controlling age-related declines in skeletal muscle regenerative potential. Taken together, successful completion of these studies may provide a foundation for the identification of novel ECM targets in the treatment of skeletal muscle injuries for a geriatric population. More broadly, an improved insight into how age-associated alterations in biomechanical, architectural and dynamic ECM properties direct MuSC function will expand our fundamental understanding of aging and stem cell biology.

摘要受伤或手术导致的骨骼肌创伤通常会导致显著的功能下降在老年人中。这些下降至少部分归因于肌肉愈合失败。肌肉再生是主要由肌肉干细胞或“卫星”细胞（MuSC）的作用决定，通常随着年龄的增长表现出相当大的功能障碍。根据干细胞“利基” 概念，干细胞反应在很大程度上是由生物物理和生物化学线索，来自周围的微环境事实上，扩大对微环境影响的认识，干细胞的行为导致了最近生物启发和工程化细胞外基质（ECM）方法用于治疗骨骼肌损伤。然而，仍然缺乏一个深入的了解天然ECM的致病性指导特征是否以及如何破坏MuSC 功能和骨骼肌再生。虽然很明显MuSC的激活、自我更新、增殖和分化的影响，物理和动态生态位的相互作用，机械的理解，年龄相关的ECM改变对骨骼肌再生能力的直接影响是未知的。这个项目的首要目标是检验我们的中心假设，即与年龄有关的生物物理学骨骼肌ECM的改变促进MuSC中的纤维化转化，最终驱动骨骼肌再生受损。此外，我们假设这些致病性生物物理通过机械刺激可以至少部分地恢复变化。为了实现这一目标，我们将采用集成方法，包括尖端的超分辨率成像和3D组织工程方法，以解决两个具体目标。目标1研究将测量、操纵和模拟年轻和老年骨骼肌ECM的生物物理特性，以剖析年龄相关的影响，对MuSC命运的结构和弹性ECM修饰。目标2研究将确定机械刺激调节老化ECM的生物物理性质以促进MuSC肌原性，肌肉再生这些目标的成功实现将进一步加深我们对1）本机ECM对MuSC谱系规范的教学能力，2）这些教学能力如何能力随时间变化，3）控制与年龄相关的骨骼肌功能下降的分子机制肌肉再生潜能总之，成功完成这些研究可以提供一个在老年人骨骼肌损伤的治疗中鉴定新的ECM靶点的基础人口更广泛地说，一个更好的洞察如何与年龄相关的生物力学变化，架构和动态ECM属性直接MuSC功能将扩展我们对衰老和干细胞生物学。