Mature & Aging Tendons: Extracellular Matrix Interactions in the Injury Response

描述(申请人提供)：本研究的总体目标是确定在成熟肌腱损伤修复反应过程中核心蛋白聚糖和双聚糖在结构和功能重建中的协同调节作用(S)，并确定衰老对核心蛋白聚糖/双聚糖介导的肌腱修复调节的影响。肌腱结构-功能关系的分析提供了一个可以定量评估细胞外基质分子及其相互作用的调节作用的框架。我们假设肌腱的损伤反应包括正常发育序列的部分重现。这包括Biglycan和Decorin的差异表达，提供了重建结构和功能所需的协调调控相互作用。此外，在老化过程中，肌腱不能重现正常的SLRP表达模式，从而影响结构和功能的重建(即，老化的肌腱将不能忠实地重现正常的差异表达模式)。为了验证这些假说，我们将分析Decorin和Biglycan表达的变化对成熟、衰老和老龄小鼠指长屈肌(FDL)肌腱伤口修复的影响。这些研究将利用我们新的FDL肌腱损伤模型。SLRP的表达将使用核心蛋白聚糖缺失、Biglycan缺失、复合突变体和野生型小鼠来操纵。将使用生物力学、生化、免疫化学和结构分析对基质蛋白和细胞因子的力学和组织特性以及轮廓进行定量评估，提供重要的新数据。本研究的具体目的是：1：确定Biglycan和Decorin在成熟、衰老和老年肌腱损伤修复反应中对肌腱生物力学性能恢复的不同调节功能(S)；目的2：确定Biglycan和Decorin在损伤相关表达模式；肌腱损伤后的组织和成分措施；以及Decorin和Biglycan在成熟、衰老和老龄小鼠损伤后肌腱结构重建中的调节作用；目的3：通过多元回归分析确定成熟、衰老和老年FDL肌腱损伤后生物力学性质与组织和成分措施的关系。这些分析将提供对核心蛋白和二聚糖在损伤修复反应中的调节作用的基本理解。此外，我们将定义一个定量的结构-功能模型，在成熟、老化和老化的肌腱中涉及这些SLRP的相互作用。这些信息不仅将阐明导致这些变化的机制，而且还将为进一步研究这些SLRP的对比和潜在的代偿作用提供一个框架，这可能有助于设计改进的肌腱损伤治疗方式。此外，明确功能性肌腱再生过程中的调控相互作用将为功能性肌腱再生的组织工程奠定基础。公共卫生相关性：本申请的重点是阐明涉及特定细胞外基质成分的相互作用在肌腱损伤的反应以及它们随着肌腱老化而发生的功能变化中的调节作用(S)。在运动、工作或衰老过程中，肌腱损伤会导致严重的疼痛和残疾，导致巨大的医疗费用、工作损失和生活质量下降。

DESCRIPTION (provided by applicant): The overall aim of this study is to determine the coordinate regulatory role(s) of decorin and biglycan in the re- establishment of structure and function during the repair response to injury in mature tendons and to define the effects of aging on decorin/biglycan mediated regulation of tendon repair. The analysis of tendon structure- function relationships provides a framework where the regulatory roles of extracellular matrix molecules and their interactions can be quantitatively evaluated. We hypothesize that the injury response in tendon involves a partial recapitulation of the normal developmental sequence. This includes the differential expression of biglycan and decorin providing the coordinate regulatory interactions required for re-establishment of structure and function. In addition, during aging, the tendon is unable to recapitulate the normal SLRP expression patterns thereby compromising the re-establishment of structure and function (i.e., the aged tendons will not be able to faithfully recapitulate the normal differential expression pattern). To test these hypotheses, we will analyze the effects of changes in decorin and biglycan expression on repair of flexor digitorum longus (FDL) tendon wounds in mature, aging and aged mice. These studies will utilize our novel injury model of the FDL tendon. SLRP expression will be manipulated using decorin-null, biglycan-null, compound mutant and wild type mice. The mechanical and organizational properties, as well as profiles of matrix proteins and cytokines will be quantitatively evaluated using biomechanical, biochemical, immunochemical and structural analyses, providing significant new data. The specific aims are to: Aim 1: Determine the differential regulatory function(s) of biglycan and decorin on restoration of biomechanical properties during the repair response to FDL tendon injury in mature, aging and aged tendons; Aim 2: Define injury-associated expression patterns of biglycan and decorin; organizational and compositional measures of tendons after injury; and the regulatory roles of decorin and biglycan in re-establishment of tendon structure after injury in mature, aging and aged mice; Aim 3: Identify relationships between biomechanical properties and organizational and compositional measures in response to injury using multiple regression analyses in mature, aging and aged FDL tendons. These analyses will provide a fundamental understanding of the regulatory roles of decorin and bigylcan in the repair response to injury. In addition, we will define a quantitative structure-function model of interactions involving these SLRPs in mature, aging and aged tendons. This information will not only elucidate mechanisms responsible for the changes, but will also provide a framework for further investigation into the contrasting and potentially compensatory roles of these SLRPs that may aid in the design of improved treatment modalities for tendon injuries. In addition, defining the regulatory interactions involved in the regeneration of a functional tendon will provide a foundation for the tissue engineering of functional replacements. PUBLIC HEALTH RELEVANCE: The focus of this application is to elucidate the regulatory role(s) of interactions involving specific extracellular matrix components in the response to tendon injury as well as in their functional alterations with tendon aging. In sports, at work, or due to aging processes, tendon injuries cause significant pain and disability, resulting in enormous healthcare costs, loss of work, and a decrease in the quality of life.