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

成熟

• 批准号: 8132164
• 负责人: DAVID E BIRK
• 金额: $ 3.79万
• 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/8132164
• 关键词: Age; Aging; Aging-Related Process; Biochemical; Biomechanics; Data; Development; Extracellular Matrix; Flexor; Foundations; Growth; Healed; 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; public health relevance; 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）：本研究的总体目的是确定核心蛋白聚糖和双糖蛋白聚糖在成熟肌腱损伤修复反应期间重建结构和功能中的协调调节作用，并确定老化对核心蛋白聚糖/双糖蛋白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框架，其中细胞外基质分子的调节作用及其相互作用可以定量评估。我们推测，肌腱损伤反应涉及正常发育序列的部分重演。这包括双糖链蛋白聚糖和核心蛋白聚糖的差异表达，提供重建结构和功能所需的协调调节相互作用。此外，在老化期间，肌腱不能重现正常的SLRP表达模式，从而损害结构和功能的重建（即，老化的肌腱将不能忠实地再现正常的差异表达模式）。为了验证这些假设，我们将分析核心蛋白聚糖和双糖蛋白聚糖表达的变化对成熟、衰老和老年小鼠趾长屈肌腱（FDL）损伤修复的影响。这些研究将利用我们新的损伤模型的FDL肌腱。将使用核心蛋白聚糖缺失、双糖链聚糖缺失、化合物突变体和野生型小鼠操纵SLRP表达。的机械和组织特性，以及配置文件的基质蛋白和细胞因子将使用生物力学，生物化学，免疫化学和结构分析进行定量评估，提供重要的新数据。具体目标是：目标1：确定双糖链蛋白聚糖和核心蛋白聚糖在成熟、老化和老化肌腱中对FDL肌腱损伤的修复反应期间对生物力学性质恢复的差异调节功能;目的2：定义双糖链蛋白聚糖和核心蛋白聚糖的损伤相关表达模式;损伤后肌腱的组织和组成测量;以及核心蛋白聚糖和双糖链蛋白聚糖在成熟、衰老和老年小鼠肌腱损伤后结构重建中的调节作用;目的3：在成熟、老化和老化的FDL肌腱中，使用多元回归分析确定生物力学特性与组织和成分措施之间的关系。这些分析将提供一个基本的理解核心蛋白聚糖和双聚糖在损伤修复反应中的调节作用。此外，我们将定义一个定量的结构-功能模型的相互作用，涉及这些SLRP在成熟，老化和老化肌腱。这些信息不仅将阐明负责的变化的机制，但也将提供一个框架，进一步调查这些SLRP的对比和潜在的补偿作用，可能有助于设计改进的治疗方式肌腱损伤。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的组织工程提供基础。公共卫生关系：本申请的重点是阐明涉及特异性细胞外基质组分的相互作用在对肌腱损伤的反应中以及在其随肌腱老化的功能改变中的调节作用。在运动中，在工作中，或由于衰老过程，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。