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

成熟

• 批准号: 8016050
• 负责人: DAVID E BIRK
• 金额: $ 40.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-05 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016050
• 关键词: Aging; Aging-Related Process; Biochemical; Biomechanics; Data; Development; Extracellular Matrix; Flexor; Foundations; Growth; Healed; Health; Health Care Costs; Injury; Investigation; Leucine; Measures; Mechanics; Mediating; Modality; Modeling; Mus; Natural regeneration; Pain; Pattern; Property; Proteins; Proteoglycan; Quality of life; Regression Analysis; Regulation; Role; Sports; Staging; Structure; Structure-Activity Relationship; Tendon Injuries; Tendon structure; Testing; Tissue Engineering; Tissues; Wild Type Mouse; Work; age effect; aged; aging population; biglycan; cytokine; decorin; design; disability; healing; improved; mutant; novel; repaired; response; response to injury; restoration; therapy design

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.

描述（由申请人提供）：这项研究的总体目的是确定在成熟肌腱对损伤的修复响应过程中，在重新建立结构和功能方面的坐标调节作用，并定义衰老对DecorIn/Biglycan介导的肌腱修复的调节的影响。肌腱结构 - 功能关系的分析提供了一个框架，其中可以对细胞外基质分子的调节作用及其相互作用进行定量评估。我们假设肌腱中的损伤反应涉及正常发育序列的部分概括。这包括Biglycan和Decorin的差异表达，提供了重新建立结构和功能所需的坐标调节相互作用。此外，在衰老期间，肌腱无法概括正常的SLRP表达模式，从而损害了结构和功能的重新建立（即，老年肌腱将无法忠实地概括正常的差分表达模式）。为了检验这些假设，我们将分析成熟，衰老和衰老小鼠中屈肌长长（FDL）肌腱伤口修复屈肌（FDL）伤口的变化的影响。这些研究将利用我们的新型FDL肌腱损伤模型。 SLRP表达将使用Decorin-null，Biglycan-Null，复合突变体和野生型小鼠进行操纵。将使用生物力学，生化，免疫化学和结构分析进行定量评估基质蛋白和细胞因子的机械和组织特性以及基质蛋白和细胞因子的谱。具体目的是：目标1：在修复对FDL肌电肌损伤的恢复中，在成熟，衰老和衰老肌腱中，确定Biglancan和Decorin的差异调节功能； AIM 2：定义与损伤相关的表达模式的大型群和装饰；受伤后的组织和组成措施； Decorin和Biglancan在成熟，衰老和衰老的小鼠受伤后重建肌腱结构中的调节作用； AIM 3：使用成熟，衰老和老化的FDL肌腱中的多重回归分析，确定生物力学特性与组织和组成措施之间的关系。这些分析将提供对Decorin和Bigylcan在修复伤害反应中的调节作用的基本理解。此外，我们将定义涉及这些SLRP的相互作用的定量结构 - 功能模型，该模型涉及成熟，衰老和衰老肌腱。该信息不仅将阐明负责变化的机制，而且还将提供一个框架，以进一步研究这些SLRP的对比和潜在的补偿作用，这些作用可能有助于设计改善肌腱损伤的治疗方式。此外，定义功能肌腱再生所涉及的调节相互作用将为功能替代的组织工程提供基础。公共卫生相关性：该应用的重点是阐明涉及肌腱损伤及其肌腱衰老的功能变化中涉及特定细胞外基质成分的相互作用的调节作用。在运动，工作中或由于衰老过程中，肌腱受伤会导致严重的疼痛和残疾，导致巨大的医疗保健成本，工作损失以及生活质量的下降。