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Multiscale tendon damage and aberrant cellular responses in an in vivo model of tendinosis

肌腱变性体内模型中的多尺度肌腱损伤和异常细胞反应

基本信息

批准号：
10343017
负责人：
DAWN M ELLIOTT
金额：
$ 49.09万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-22 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343017
关键词：
Ablation Actins Acute Animal Model Architecture Area Automobile Driving Cell Communication Cell Density Cell Shape Cells Chronic Clinical Clinical Research Collagen Collagen Fiber Collagen Type III Cytoskeleton Data Disease Exhibits F-Actin Fiber Foundations Goals Human Image Intervention Knowledge Measures Mechanics Modeling Modulus Molecular Natural regeneration Outcome Pain Phenotype Physiological Processes Physiology Positioning Attribute Production Proteins Proteoglycan Rattus Rehabilitation therapy Role Signal Transduction Slide Study models Tendinopathy Tendon structure Testing Time Tissues Tropomyosin achilles tendon depolymerization design fiber cell in vivo in vivo Model mechanical load mechanical properties mechanical signal mechanotransduction molecular scale nanoscale novel polymerization pre-clinical prevent response therapy design transmission process

项目摘要

Project Summary Tendon overuse initiates mechanical damage that leads to chronic tendinosis (degeneration) and tendinopathy (clinical presentation with pain), which are common and notoriously difficult to treat. Despite the widely accepted role of loading in tendinosis, the structural, mechanical, and cellular mechanisms by which loading leads to initiation and progressive damage in tendinosis remain unknown. We hypothesize that overload causes micro-scale structural and mechanical damage, which alters load transmission to cells, driving the multi-scale structural and molecular progression of tendinosis in a vicious cycle. To determine the mechanisms involved in tendinosis, a preclinical in vivo animal model of tendon overuse and multiscale assessments of tendon structural and mechanical damage and interrogation of cellular mechanotransduction and intracellular signaling mechanisms are all required. This is because the physiological processes in tendinosis involve tissue-scale tendon loading that is transferred to the micro-, nano-, and molecular-scale, where microstructural damage and cellular mechanotransduction signaling occurs. Our team has recently established a model of tendinosis using rat synergist ablation (SynAb), where we remove the Achilles tendon, which overloads the synergistic plantaris tendon without directly injuring it. Our pilot data exhibit hallmark features of human tendinosis (increased area, collagen disorganization, proteoglycan accumulation, collagen Type III production, and reduced tensile modulus). Our long-term goal is to enable interventions for tendon regeneration and rehabilitation to treat tendinopathy and prevent its progression. The objective of this proposal is to determine the mechanisms responsible for onset and progression of tendinosis in the SynAb model of tendon overuse in the following aims: Aim 1: Assess the multiscale structural changes following the onset and progression of tendinosis. Aim 2: Quantify the multiscale mechanical properties and damage following the onset and progression of tendinosis. Aim 3: Interrogate changes in tenocyte mechanoresponse and cytoskeleton during tendon overload. This study will determine the mechanisms responsible for the multiscale damage in overuse tendinosis and establish these in the context of key hallmarks of human tendinosis using a preclinical in vivo model. Quantifying multiscale damage and cellular mechanisms by which loading leads to tendinosis is critical for designing and evaluating interventions to prevent and treat tendinopathy.

项目总结