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

• 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
• 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

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.

项目摘要 肌腱过度使用会引发机械损伤，导致慢性肌腱病(退行性变)和 肌腱病(临床表现为疼痛)，这是常见的，众所周知的难以治疗。尽管 广泛接受的负荷在肌腱病中的作用，其结构、力学和细胞机制 负荷导致肌腱病的起始和进行性损害仍不清楚。我们假设 超载导致微尺度的结构和机械损伤，从而改变载荷传递 细胞，在恶性循环中驱动肌腱病的多尺度结构和分子进展。 为了确定肌腱病的发病机制，建立了一种临床前的肌腱活体动物模型 对肌腱结构和机械损伤的过度使用和多尺度评估以及对 细胞机械转导和细胞内信号机制都是必需的。这是因为 肌腱病的生理过程包括组织规模的肌腱负荷，这些负荷被转移到微观的， 纳米和分子尺度，微结构损伤和细胞机械转导信号发生的地方。 我们的团队最近使用大鼠协同消融(SynAb)建立了一种肌腱病模型，在该模型中，我们 去除跟腱，这会使协同的足底肌腱负荷过重，而不会直接损伤它。我们的 试验数据显示了人类肌腱病的显著特征(面积增大，胶原蛋白紊乱， 蛋白多糖的积累、III型胶原的产生和拉伸模数的降低)。 我们的长期目标是使肌腱再生和康复干预能够治疗肌腱病。 并阻止其发展。这项建议的目标是确定负责的机制 在肌腱过度使用的SynAb模型中，肌腱病的发生和进展有以下目的： 目的1：评估肌腱病发生和发展后的多尺度结构变化。 目标2：量化发病和发展后的多尺度力学特性和损伤 肌腱病的症状。 目的3：探讨肌腱超负荷时肌腱细胞力学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害的机制和 使用临床前的活体模型，在人类肌腱病的关键特征的背景下建立这些。 量化多尺度损伤和负荷导致肌腱病的细胞机制对 设计和评估预防和治疗肌腱病的干预措施。