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: 10687977
• 负责人: DAWN M ELLIOTT
• 金额: $ 47.51万
• 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/10687977
• 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; Multiscale Mechanics; Natural regeneration; Outcome; Pain; Phenotype; Physiological Processes; Physiology; Polymers; 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 肌腱过度使用会引起机械损伤，从而导致慢性肌腱病（变性）和 肌腱病（疼痛的临床表现），这是常见且臭名昭著的治疗。尽管有 负荷在肌腱病，结构，机械和细胞机制中的广泛接受作用 负载导致肌腱病的起始和进行性损害尚不清楚。我们假设这一点 超负荷会导致微尺度结构和机械损害，从而改变负载传输到 细胞，在恶性循环中驱动肌腱病的多尺度结构和分子进展。 为了确定肌腱病涉及的机制，肌腱的临床前动物模型 肌腱结构和机械损伤的过度使用和多尺度评估 需要细胞机械传导和细胞内信号传导机制。这是因为 在 纳米和分子尺度，其中发生了微结构损伤和细胞机械传导信号传导。 我们的团队最近使用Rat Synergist消融（Synab）建立了肌腱病模型，我们在这里 去除跟腱肌腱，该肌腱使协同的Plantaris肌腱超载而无需直接伤害它。我们的 试验数据具有人类肌腱病的标志性特征（胶原蛋白的增加，胶原蛋白混乱， 蛋白聚糖的积累，III型胶原蛋白产生和张力模量减少）。 我们的长期目标是实现肌腱再生和康复的干预措施，以治疗肌腱病 并防止其进展。该提案的目的是确定负责的机制 在以下目的的肌腱模型中，肌腱病模型中的肌腱病的发作和进展： 目标1：评估肌腱病的发作和进展后的多尺度结构变化。 目标2：量化发作和进展后的多尺度机械性能和损害 肌腱病。 AIM 3：在肌腱超负荷期间，询问Tenocyte机械响应和细胞骨架的变化。 这项研究将确定导致过度使用肌腱病多尺度损害的机制和 使用临床前体内模型的人类肌腱病的关键标志建立这些。 量化负荷导致肌腱病至关重要的多尺度损害和细胞机制至关重要 设计和评估干预措施，以预防和治疗肌腱病。

项目成果

Stress deprivation of tendon explants or Tpm3.1 inhibition in tendon cells reduces F-actin to promote a tendinosis-like phenotype.

• DOI: 10.1091/mbc.e22-02-0067
• 发表时间: 2022-12-01
• 期刊: MOLECULAR BIOLOGY OF THE CELL
• 影响因子: 3.3
• 作者: Inguito, Kameron L.;Schofield, Mandy M.;Faghri, Arya D.;Bloom, Ellen T.;Heino, Marissa;West, Valerie C.;Ebron, Karl Matthew M.;Elliott, Dawn M.;Parreno, Justin
• 通讯作者: Parreno, Justin