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

项目摘要 肌腱过度使用引发机械损伤，导致慢性肌腱病（退化）， 肌腱病（临床表现为疼痛），这是常见的，众所周知，难以治疗。 广泛接受的作用负荷肌腱，结构，机械和细胞机制， 负荷导致肌腱病的开始和进行性损伤仍然未知。我们假设 过载导致微观结构和机械损伤，这改变了载荷传递， 细胞，推动肌腱病的多尺度结构和分子进展的恶性循环。 为了确定参与肌腱病的机制，临床前体内肌腱动物模型 肌腱结构和机械损伤的过度使用和多尺度评估， 细胞机械传导和细胞内信号传导机制都是必需的。这是因为 肌腱病中的生理过程涉及组织尺度的肌腱负荷， 纳米和分子尺度，其中发生微结构损伤和细胞机械转导信号。 我们的团队最近建立了一个使用大鼠肌腱消融（SynAb）的肌腱病模型， 移除跟腱，这会使协同作用的跖肌腱过载而不会直接损伤它。我们的 试验数据显示了人类肌腱病的标志性特征（面积增加，胶原蛋白紊乱， 蛋白聚糖积累、III型胶原蛋白产生和降低的拉伸模量）。 我们的长期目标是使肌腱再生和康复干预治疗肌腱病 并阻止其发展。这项建议的目的是确定负责的机制 在肌腱过度使用的SynAb模型中用于肌腱变性的发作和进展，目的如下： 目的1：评估肌腱病发病和进展后的多尺度结构变化。 目的2：量化发病和进展后的多尺度力学性能和损伤 肌腱病 目的3：探讨肌腱超负荷时腱细胞机械反应和细胞骨架的变化。 这项研究将确定过度使用肌腱病多尺度损伤的机制， 使用临床前体内模型在人类肌腱病的关键标志的背景下建立这些。 量化多尺度损伤和细胞机制，通过这些机制，负荷导致肌腱变性， 设计和评估预防和治疗肌腱病的干预措施。

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.