Age-related mechanisms of altered tendon structure and function

肌腱结构和功能改变的年龄相关机制

• 批准号: 10678395
• 负责人: Alayna Loiselle
• 金额: $ 49.71万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678395
• 关键词: ATAC-seq; Address; Age; Age Months; Aging; Anabolism; Apoptosis; Attenuated; Automobile Driving; Cell Communication; Cell Death; Cell Density; Cell physiology; Cells; Cellularity; Cessation of life; Cues; Data; Drops; Elderly; Environment; Epigenetic Process; Extracellular Matrix; Flexor; Genomics; Goals; Health; Heterogeneity; Histologic; Homeostasis; Impaired healing; Impairment; Inflammatory; Injury; Locomotion; Longevity; Mechanics; Modeling; Modification; Molecular; Morphology; Mus; Pathology; Pathway interactions; Pattern; Periodicity; Phase; Phenotype; Physiological; Population; Production; Quality of life; Rejuvenation; Role; Spontaneous Rupture; Structure; Tendon Injuries; Tendon structure; Testing; Therapeutic; Tissues; age related; aged; c-myc Genes; cell age; cell dedifferentiation; efficacy evaluation; experience; functional plasticity; functional restoration; healing; improved; juvenile animal; middle age; novel strategies; novel therapeutics; pluripotency; preservation; prevent; programs; proteostasis; reparative capacity; response; single-cell RNA sequencing; skeletal; therapeutic development

During aging, tendons demonstrate substantial disruptions in homeostasis, leading to impairments in structure and function. Given the central role of tendon in appropriate skeletal locomotion and ambulation, impaired tendon function contributes to substantial declines in overall function and quality of life during aging. Moreover, aged tendons are more likely to undergo spontaneous rupture, and the healing response following injury is drastically impaired in aged tendons. Thus, there is a clear need to develop strategies to maintain tendon homeostasis and healing capacity through the lifespan. Tendon cell density sharply declines by about 12 months of age in mice, and this low cell density is retained even in geriatric tendons. Our preliminary data suggests that this decline in cellularity initiates a degenerative cascade due to insufficient production of the extracellular matrix components needed to maintain tendon homeostasis. Thus, preventing this decline in tendon cellularity has great potential for maintaining tendon health. In addition, the tenocytes that remain in aged tendon demonstrate substantial alterations in their molecular programs, relative to young tendon cells. Surprisingly, this programmatic skewing does not seem to drive additional homeostatic disruptions, but we hypothesize that it is a key driver of age-related impairments in tendon healing. Thus, reversing this programmatic skewing may restore physiological healing function to aged tendons. While the pathways that drive aging-induced tendon cell death vs. programmatic skewing are likely distinct, epigenetic modifications underly nearly every aspect of cell function. Indeed, partial epigenetic reprogramming has demonstrated tremendous potential in addressing a range of age-related pathologies. In this proposal we will test the central hypothesis that age-related tenocyte apoptosis driving tendon degeneration, and intrinsic programming shifts leading to impaired healing capacity can be prevented via partial epigenetic reprogramming. In Aim 1 we will define the multi-scale mechanisms of age-related tendon degeneration using a combination of genomics, histological, and mechanical analyses. We will then determine the efficacy of partial reprogramming to maintain tendon structure-function through the lifespan. In Aim 2 we will define how aging alters the cellular response to tendon injury using a well-established model of healing in the flexor digitorum longus tendon. We will then demonstrate that partial reprogramming can successfully restore the tenocyte functional plasticity that is required for physiological healing. Successful completion of these studies will define the tendon aging signature and establish partial reprogramming as a novel approach to maintain tendon health and healing capacity through the lifespan.

在衰老期间，肌腱表现出体内平衡的重大干扰，导致结构障碍 和功能。鉴于肌腱在适当的骨骼运动和行走中的核心作用，受损 肌腱功能在衰老过程中的总体功能和生活质量下降。而且， 老年肌腱更有可能自发破裂，受伤后的愈合反应是 老年肌腱严重受损。因此，很明显需要制定策略维护肌腱 整个生命周期内的稳态和治愈能力。肌腱细胞密度急剧下降约12 小鼠的月大，即使在老年肌腱中也保留了这种低细胞密度。我们的初步数据 表明这种细胞性下降会由于不足的产生而引发退化性级联 维持肌腱稳态所需的细胞外基质组件。因此，防止这种下降 肌腱细胞具有保持肌腱健康的巨大潜力。此外，保留在 相对于年轻的肌腱细胞，老化的肌腱显示其分子程序的实质变化。 令人惊讶的是，这种程序化偏斜似乎并没有造成其他稳态破坏，但我们 假设它是肌腱愈合中与年龄相关的损害的关键驱动力。因此，扭转了这一点 程序化偏斜可能会将生理愈合功能恢复到老年肌腱。而那道路 驱动老化引起的肌腱细胞死亡与程序化偏斜可能是不同的，表观遗传修饰 细胞功能的几乎每个方面的基础。确实，部分表观遗传重编程已经证明 在解决一系列与年龄有关的病理方面的巨大潜力。在此提案中，我们将测试中央 假设与年龄相关的替索特凋亡驱动肌腱变性和内在编程变化 通过部分表观遗传重编程可以预防导致愈合能力受损。在目标1中，我们将 使用基因组学组合来定义与年龄相关的肌腱变性的多尺度机制， 组织学和机械分析。然后，我们将确定部分重编程维护的功效 肌腱结构功能通过寿命。在AIM 2中，我们将定义衰老如何改变细胞的反应 肌腱损伤使用屈肌长肌腱中的良好愈合模型。然后我们会 证明部分重编程可以成功恢复替索特功能可塑性 生理康复所必需的。这些研究的成功完成将定义肌腱衰老 签名并建立部分重编程，作为一种保持肌腱健康和康复的新方法 整个生命周期的能力。