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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

基本信息

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
项目类别：
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

项目摘要

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.

在衰老过程中，肌腱表现出体内平衡的严重破坏，导致结构损伤