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.

在老化过程中，肌腱表现出体内平衡的实质性破坏，导致结构损伤 和功能鉴于肌腱在适当的骨骼运动和截肢中的核心作用， 肌腱功能在衰老过程中导致整体功能和生活质量的显著下降。此外，委员会认为， 老年肌腱更容易发生自发性断裂，损伤后的愈合反应是 老化的肌腱严重受损因此，有一个明确的需要，以制定战略，以保持肌腱 体内平衡和愈合能力。肌腱细胞密度急剧下降约12 月龄的小鼠中，这种低细胞密度甚至在老年肌腱中也保留。我们的初步数据 这表明，这种细胞结构的下降启动了一个退化级联，由于生产不足， 细胞外基质成分需要维持肌腱稳态。因此，防止这种下降， 肌腱细胞结构对于维持肌腱健康具有巨大潜力。此外，肌腱细胞仍然存在于 相对于年轻的肌腱细胞，老年肌腱在其分子程序中表现出实质性的改变。 令人惊讶的是，这种程序性的倾斜似乎并没有驱动额外的稳态破坏，但我们 假设它是肌腱愈合中与年龄相关的损伤的关键驱动因素。因此，扭转这一局面 程序性偏斜可以恢复老化肌腱的生理愈合功能。而那些 驱动器老化诱导的肌腱细胞死亡与程序倾斜可能是不同的，表观遗传修饰 几乎是细胞功能的各个方面的基础。事实上，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具有巨大潜力。在本建议中，我们将测试中央 假设年龄相关的腱细胞凋亡驱动肌腱变性和内在编程转移 可通过部分表观遗传重编程来预防导致愈合能力受损的疾病。在目标1中， 使用基因组学的组合来定义与年龄相关的肌腱退化的多尺度机制， 组织学和力学分析。然后，我们将确定部分重编程的有效性，以维持 肌腱的结构-功能。在目标2中，我们将定义衰老如何改变细胞反应， 肌腱损伤使用一个良好建立的愈合模型，在屈趾长肌腱。然后我们将 证明部分重编程可以成功地恢复肌腱细胞的功能可塑性， 生理愈合所需的。这些研究的成功完成将定义肌腱老化 签名并建立部分重编程作为维持肌腱健康和愈合新方法 通过寿命的能力。