Age-related mechanisms of altered tendon structure and function

在衰老过程中，肌腱表现出严重的动态平衡紊乱，导致结构损伤。 和功能。鉴于肌腱在适当的骨骼运动和步行中的核心作用，受损 肌腱功能在衰老过程中会导致整体功能和生活质量的大幅下降。此外， 老化的肌腱更有可能发生自发断裂，损伤后的愈合反应是 衰老的肌腱严重受损。因此，显然有必要制定维持肌腱的策略 在整个寿命内保持动态平衡和治愈能力。肌腱细胞密度急剧下降约12% 在老鼠几个月大的时候，这种低细胞密度即使在老年肌腱中也保持不变。我们的初步数据 表明这种细胞密度的下降启动了一种退化的级联反应，这是由于 维持肌腱动态平衡所需的细胞外基质成分。因此，防止这种下降 肌腱细胞密度对维持肌腱健康有很大的潜力。此外，留在体内的腱细胞 相对于年轻的肌腱细胞，衰老的肌腱显示其分子程序发生了实质性的变化。 令人惊讶的是，这种程序性倾斜似乎并没有推动额外的动态平衡破坏，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，扭转这一趋势 程序性偏斜可以恢复老化肌腱的生理愈合功能。而这条路径 驱动衰老诱导的肌腱细胞死亡与程序性倾斜可能是截然不同的表观遗传修饰 几乎在细胞功能的方方面面。事实上，部分表观遗传重新编程已经证明 在解决一系列与年龄相关的病理问题方面具有巨大的潜力。在本提案中，我们将测试中央 与年龄相关的肌腱细胞凋亡导致肌腱退变和内在编程改变的假说 导致受损的修复能力可以通过部分表观遗传重新编程来防止。在目标1中，我们将 结合基因组学定义与年龄相关的肌腱退行性变的多尺度机制， 组织学和力学分析。然后我们将确定部分重新编程的有效性，以保持 肌腱结构--在整个生命周期中发挥作用。在目标2中，我们将定义衰老如何改变细胞对 肌腱损伤采用成熟的指长屈肌腱愈合模型。到时候我们会的 证明部分重编程可以成功恢复腱细胞的功能可塑性，即 生理愈合所必需的。这些研究的成功完成将确定肌腱的老化 签署并建立部分重新编程作为维持肌腱健康和愈合的新方法 通过使用寿命的容量。

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.