Mechanisms of Sub-rupture Local Tendon Damage and Repair

说明(申请人提供)：肌腱病和肌腱断裂是常见的疼痛和衰弱的临床问题，与经常经历的高拉伸负荷、结构和材料不均匀以及对损伤的愈合反应不充分有关。因此，研究评估了过度使用和周期性负荷对韧带和肌腱的机械和结构退化的影响，以探讨肌腱病的发生和发展机制。肌腱的表面应变已被量化，以推断其承载能力和损伤开始或进展的可能性。对肌腱负荷的整体分子表达也进行了评估，以得出有关肌腱损伤和修复机制的结论。尽管从这些研究中获得了洞察力，但局部肌腱应变、结构损伤和局部分子对亚断裂疲劳损伤的反应之间的关系尚未建立。建立分子和结构变化与肌腱承载能力之间的直接关系将有助于深入了解肌腱损伤和修复的机制。由于体内应变测量方法和分子分析的局限性，无法评估分子反应与体内局部肌腱应变随时间变化的大小和方向之间的关系。因此，这项建议的总体目标是在体内疲劳损伤模型中量化大鼠膝盖腱的局部应变和肌腱内局部分子反应之间的关系。在疲劳负荷后，将测量肌腱的局部分子反应，并随着时间的推移确定损伤和修复的反应。将开发测量高分辨率在体肌腱应变和结构损伤的技术，这将与空间分子反应有关。这将提供缺失的力学和结构背景来解释肌腱对损伤和愈合的分子反应。评估局部而不是整体组织的力学和分子反应将有助于深入了解在整体组织分析中与亚破裂疲劳损伤修复相关的任何分子变化是源于承重区还是机械缺陷区。虽然肌腱的大量分子反应可能表明修复或重塑，但拟议研究的数据将表明，受损的机械缺陷区域是可以愈合还是只会进一步受损。随着时间的推移，评估这些关系将探索肌腱修复的机制，这可能会影响有效治疗的发展。 公共卫生相关性：肌腱病是一种常见的、使人虚弱的临床问题。这项建议的目的是量化肌腱在疲劳负荷后和随着时间的推移的应变、分子反应和结构变化之间的局部关系，以确定损伤和修复的反应。这将提供缺失的力学和结构背景来解释肌腱对损伤和修复的分子反应。

DESCRIPTION (provided by applicant): Tendinopathy and tendon rupture are common painful and debilitating clinical problems associated with frequently experienced high tensile loads, structural and material inhomogeneity, and inadequate healing responses to injury. Studies have therefore evaluated mechanical and structural degeneration of ligaments and tendons in response to overuse and cyclic loading to investigate mechanism of initiation and progression of tendinopathy. Surface strain in the tendon has been quantified to extrapolate its load bearing capacity and likelihood of damage initiation or progression. Overall molecular expression has also been evaluated in response to tendon loading to make conclusions regarding mechanisms of tendon damage and repair. Despite insight gained from these studies, the relationship between local tendon strain, structural damage, and the local molecular response to sub-rupture fatigue damage has not been established. Establishing the direct relationship between the molecular and structural changes and the load bearing capacity of the tendon will lend insight into the mechanisms of tendon damage and repair. Limitations of in-vivo strain measurement methods and molecular analyses preclude evaluation of the relationship between the molecular response and the magnitude and direction of the local tendon strain in-vivo over time. Therefore the general objective of this proposal is to quantify the relationship between the local strain in rat patellar tendons and the local molecular response within the tendon in an in-vivo fatigue damage model. The local molecular response of the tendon will be measured after fatigue loading, and over time to determine the response to damage and repair. Techniques will be developed to measure high resolution in-vivo tendon strain and structural damage which will be related to the spatial molecular response. This will provide the missing mechanical and structural context to interpret the molecular response of tendon to damage and healing. Evaluating the local instead of bulk tissue mechanics and molecular response will provide insight into whether any molecular changes associated with sub-rupture fatigue damage repair in bulk tissue analysis stem from load bearing or mechanically deficient regions. While the bulk molecular response of the tendon may be indicative of repair or remodeling, data from the proposed study will show whether a damaged mechanically deficient region can heal or only be further damaged. Evaluating these relationships over time will explore mechanisms of tendon repair which could influence development of effective treatment. PUBLIC HEALTH RELEVANCE: Tendinopathy is a common and debilitating clinical problem. The goal of this proposal is to quantify the local relationship between strain, molecular response, and structural changes within the tendon in-vivo after fatigue loading and over time to determine the response to damage and repair. This will provide the missing mechanical and structural context to interpret the molecular response of the tendon to damage and repair.