Research Project 1

总结 目前跟腱病的治疗策略寻求调节肌腱力学环境， 促进愈合和再生。然而，对肌腱病缺乏基本的了解， 机械生物学限制了康复策略的优化，阻碍了有针对性的机械生物学的发展。 治疗学该提案将使用人类肌腱病的正交实验来解决这些差距， 大鼠过度使用和机械小鼠模型。拟议的研究将建立一个框架， 机制策略和识别新的信号转导靶点。肌腱病，特别是由 过度使用通常会导致组织微损伤。这种微损伤反过来又损害了拉伸力的传递， 机械信号通过组织，导致内源性肌腱细胞负荷不足。我们的初步 数据显示腱细胞对腱去张力表现出双相反应。放松导致 细胞骨架张力和机械传导信号的短暂损失，导致基质的上调 降解酶如基质金属蛋白酶。随后，肌腱细胞试图重新拉紧 基质通过细胞骨架收缩和基质重组。这种双相反应代表了一种新的 理解肌腱病的发展、进展和转化干预的框架。在 在拟议的研究中，我们将1）确定肌腱病如何影响跟腱张力稳态 在疾病谱中，2）定义机械传导机制，3）确定如何 康复负荷恢复了跟腱张力稳态的平移影响。利用我们的专业知识， 肌腱形成和肌腱病（Dyment）和机械生物学（Dyment/Boerckel），这个翻译项目将 提供了一个全面的理解机械转导机制，驱动异常和 跟腱病期间的慢性基质重塑，定义对照组中的机械反应基准， 可以预测临床患者结果的测定，并为下一代药物鉴定有效的药物靶点。 量身定制的机械治疗，以补充目前的黄金标准的物理治疗和手术。

SUMMARY Current treatment strategies for Achilles tendinopathy seek to modulate the tendon mechanical environment to promote healing and regeneration. However, a lack of fundamental understanding of tendinopathic mechanobiology limits optimization of rehabilitation strategies and impedes development of targeted mechano- therapeutics. This proposal will address these gaps using orthogonal experiments across human tendinopathy, rat overuse, and mechanistic mouse models. The proposed studies will establish a framework to inform mechanotherapeutic strategies and identify novel signaling targets. Tendinopathy, particularly caused by overuse, often results in tissue microdamage. This microdamage, in turn, impairs transmission of tensile mechanical signals through the tissue, resulting in under-loading of endogenous tendon cells. Our preliminary data show that tendon cells exhibit a biphasic response to tendon de-tensioning. De-tensioning causes a transient loss in cytoskeletal tension and mechanotransductive signaling, resulting in upregulation of matrix degrading enzymes like matrix metalloproteinases. Subsequently the tendon cells attempt to re-tension the matrix by cytoskeletal contraction and matrix re-organization. This biphasic response represents a novel framework for understanding the development, progression, and translational intervention of tendinopathy. In the proposed studies, we will 1) determine how tendinopathic disease impacts Achilles tensional homeostasis across the spectrum of disease, 2) define the mechanotransductive mechanisms, and 3) determine how rehabilitative loading restores Achilles tensional homeostasis for translational impact. Using our expertise in tenogenesis and tendinopathy (Dyment) and mechanobiology (Dyment/Boerckel), this translational project will provide a comprehensive understanding of the mechanotransductive mechanisms that drive aberrant and chronic matrix remodeling during Achilles tendinopathy, define mechano-response benchmarks in controlled assays that may predict clinical patient outcome, and identify potent drug targets for the next generation of tailored mechanotherapeutics to complement the current gold standards of physical therapy and surgery.