An interdisciplinary and integrative study of tendinopathy

描述（由申请人提供）：慢性疼痛性肌腱疾病，称为肌腱病，影响数百万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引起的反复微损伤导致肌腱基质修复失败。然而，缺乏科学数据来支持这一猜测。此外，尽管近年来对肌腱病进行了深入的研究，但肌腱炎症是否导致肌腱退行性变仍然是一个悬而未决的问题，这在肌腱病的晚期经常出现。因此，该项目的中心假设是，慢性机械负荷放置在肌腱诱导微损伤和炎症，导致肌腱基质的退行性变化。为了验证这一中心假设，我们提出了以下四个具体目标：1）确定通过跑步机跑步的慢性机械负荷对小鼠肌腱的影响，特别是肌腱微损伤，巨噬细胞浸润，肌成纤维细胞的存在和炎症介质的表达; 2）表征来自通过跑步机跑步慢性负荷的小鼠的肌腱成纤维细胞的合成代谢和分解代谢基因和蛋白质表达谱; 3）确定肌腱持续负荷炎症是否导致体内肌腱的额外退行性变化;以及4）确定减少肌腱炎症是否改善体内肌腱的生物学、生物化学和生物力学性质。基于我们以前的肌腱炎研究，主要集中在体外模型研究，我们将扩大我们的研究，肌腱病的动物模型研究。使用跨学科和综合的方法，我们将调查肌腱病变的发育机制，通过表征肌腱的合成代谢和分解代谢的变化，以及由于体内慢性机械负荷导致的肌腱成纤维细胞表型表达的变化。此外，我们将确定减少肌腱炎症对愈合肌腱的生物学、生物化学和生物力学特性的影响。该项目的科学发现将提高我们对肌腱病确切致病过程的理解。他们还将帮助制定肌腱病临床管理的新方案，并设计新的预防策略，如抗炎治疗，以减少工作场所和运动环境中肌腱病的发病率。

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.