An interdisciplinary and integrative study of tendinopathy

描述(申请人提供)：慢性疼痛的肌腱疾病，称为肌腱病，影响数以百万计的美国人的职业和运动环境。据推测，肌腱病可能是由于机械负荷造成的重复微损伤导致肌腱基质修复失败所致。然而，缺乏支持这一猜测的科学数据。此外，尽管近年来对肌腱病进行了大量的研究，但肌腱炎症是否会导致肌腱退行性变仍是一个悬而未决的问题，而肌腱退行性变通常见于肌腱病的晚期。因此，这个项目的中心假设是，施加在肌腱上的慢性机械负荷会导致微损伤和炎症，从而导致肌腱基质的退行性变化。为了验证这一中心假说，我们提出了以下四个具体目标：1)确定通过跑步机跑步对小鼠肌腱的慢性机械负荷的影响，特别是肌腱微损伤、巨噬细胞的渗透、肌成纤维细胞的存在以及炎症介质的表达；2)表征通过跑步机跑步慢性负荷的小鼠肌腱成纤维细胞的合成和分解代谢基因和蛋白的表达谱；3)确定持续的炎症负荷是否会导致体内肌腱的额外退行性变化；以及4)确定减轻肌腱炎症是否可以改善体内肌腱的生物、生化和生物力学性质。我们之前的肌腱炎症研究主要集中在体外模型研究，在此基础上，我们将把研究扩展到肌腱病的动物模型研究。我们将利用跨学科和综合的方法，通过表征肌腱合成代谢和分解代谢的变化以及肌腱成纤维细胞在体内慢性机械负荷下表型表达的变化，来研究肌腱病的发展机制。此外，我们还将确定减轻肌腱炎症对愈合肌腱的生物、生化和生物力学性能的影响。该项目的科学发现将提高我们对肌腱病的确切致病过程的理解。它们还将帮助设计肌腱病临床治疗的新方案，并设计新的预防策略，如消炎治疗，以减少工作场所和运动环境中的肌腱病发生率。

DESCRIPTION (provided by applicant): Chronic, painful tendon conditions, known as tendinopathy, affect millions of Americans in both occupational and athletic settings. It has been speculated that tendinopathy may result from a failure to repair tendon matrix in response to repeated microinjuries by mechanical loading. However, scientific data to support this speculation are lacking. Also, in spite of intensive research on tendinopathy in recent years, it is still an open question for debate whether tendon inflammation leads to tendon degeneration that is often seen in the late stage of tendinopathy. Thus, the central hypothesis of this project is that chronic mechanical loading placed on the tendon induces microinjuries and inflammation, which leads to degenerative changes in the tendon matrix. To test this central hypothesis, we propose the following four specific aims: 1) to determine the effects of chronic mechanical loading via treadmill running on mouse tendons in vivo, specifically tendon microinjuries, infiltration of macrophages, presence of myofibroblasts, and expression of inflammatory mediators; 2) to characterize the anabolic and catabolic gene and protein expression profiles of tendon fibroblasts from mice that are chronically loaded via treadmill running; 3) to determine whether the continued loading of tendons with inflammation leads to additional degenerative changes in tendons in vivo; and 4) to determine whether reducing tendon inflammation improves the biological, biochemical, and biomechanical properties of tendons in vivo. Building upon our previous tendinitis research, which primarily focused on in vitro model studies, we will expand our research to animal model studies of tendinopathy. Using interdisciplinary and integrative approaches, we will investigate the developmental mechanisms of tendinopathy by characterizing changes in the anabolic and catabolic metabolisms of the tendon as well as changes in the phenotypic expression of tendon fibroblasts due to chronic mechanical loading in vivo. In addition, we will determine the effect of reducing tendon inflammation on the biological, biochemical, and biomechanical properties of the healing tendon. The scientific findings of this project will improve our understanding of the precise pathogenic processes of tendinopathy. They will also aid in devising new protocols for the clinical management of tendinopathy and in designing new preventive strategies, such as anti-inflammation therapy, to reduce the incidence of tendinopathy in the workplace as well as in athletic settings.