Mouse Models for SLRP Roles in Tendon Aging and Impaired Healing in Aging Tendons

SLRP 在肌腱老​​化和老化肌腱愈合受损中的作用的小鼠模型

• 批准号: 9016494
• 负责人: DAVID E BIRK
• 金额: $ 33.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9016494
• 关键词: Address; Age; Aging; Area; Biological Models; Clinical; Complement; Coupled; Data; Development; Exhibits; Extracellular Matrix; Flexor; Goals; Growth; Growth and Development function; Healed; Health; Healthcare Systems; Impaired wound healing; Inflammatory; Injury; Investigation; Knock-out; Knockout Mice; Leucine; Measures; Mechanics; Mediating; Modality; Modeling; Mus; Pain; Pattern; Phase; Phenotype; Process; Property; Proteoglycan; Quality of life; Regulation; Role; Specificity; Structure; Tendon Injuries; Tendon structure; Time; Work; age effect; aged; aging population; biglycan; decorin; design; differential expression; disability; healing; improved; injury and repair; innovation; mouse model; novel; repaired; response; response to injury; tendon development

 DESCRIPTION (provided by applicant): Tendon injuries are a common problem exacerbated in the aging population. Significant pain and disability are associated with these injuries resultig in decreased quality of life, loss of work and independence. Interactions involving small leucine-rich proteoglycans (SLRPs) and other matrix molecules are central to the regulation of the hierarchical assembly of tendon, as well as in the establishment or re-establishment of tendon mechanical function. The class I SLRPs, decorin and biglycan, exhibit alterations in expression during growth, aging and in the injury response. The absence of decorin ameliorates the mechanical and fibril parameter changes associated with aging and is detrimental to the tendon injury response. These data suggest critical regulatory roles for SLRPs in tendon. Unfortunately, progress in this area has been limited by the model systems available. Use of conventional knockout mice does not allow control of temporal or spatial specificity and secondary and compensatory effects cannot be controlled. To address this, we developed inducible-null mouse models to isolate age and injury specific effects while avoiding confounding issues. The overall goal of this proposal is to delineate the coordinated mechanisms whereby alterations in decorin and biglycan expression influence the detrimental effects seen during the aging, as well as in injury and repair processes. During tendon aging, the interactions involving SLRPs that result in an impaired injury response will be defined. Our general hypothesis is that tendon aging and the impaired age-associated response to tendon injuries are the result of similar SLRP-mediated mechanisms. Specifically, sequential changes in the differential expression of biglycan and decorin provide coordinate regulatory interactions required for re-establishment of tendon structure and function. These patterns are disrupted with aging resulting in altered structure, function and repair ability. The study aims are: Aim 1: Define mechanisms whereby SLRPs influence tendon aging. Aim 2: Define the mechanism whereby aging alters the regulatory role(s) of SLRPs in the tendon injury response. Aim 3: Determine the differential effect(s) of the addition of SLRPs in the tendon injury response with aging. We will utilize our novel inducible mouse models and exploit their temporal specificity to systematically define the roles of decorin and biglycan in tendon aging and in the associated altered injury response. This will be coupled with systemic administration of SLRPs to generate four distinct compositions for analyses of the mechanistic roles. Our flexor tendon injury model coupled with sophisticated and innovative measures of mechanical and organizational properties, together with compositional profiles will be used to derive a mechanistic understanding of these responses. Further, these analyses will provide a fundamental understanding of the regulatory interactions of decorin and bigylcan in aging and in the injury response. Finally, this information will provide a framework for further investigation into the contrasting and potentially synergistic roles of these SLRPs that will aid i the design of improved treatments for age associated tendon injuries.

 描述（适用提供）：肌腱损伤是老龄化人群中常见的问题。与这些伤害相关的显着疼痛和残疾导致生活质量降低，工作丧失和独立性。涉及小亮氨酸蛋白聚糖（SLRP）和其他基质分子的相互作用对于调节肌腱的分层组件以及肌腱机械功能的建立或重新建立是至关重要的。 I类SLRP，Decorin和Biglancan在生长，衰老和损伤反应中表达的变化。缺乏装饰可以改善与衰老相关的机械和原纤维参数变化，并且对肌腱损伤反应有害。这些数据表明SLRP在肌腱中的关键调节作用。不幸的是，该领域的进展受到可用模型系统的限制。传统敲除小鼠的使用不允许控制临时或空间特异性，因此无法控制次要和补偿效应。为了解决这个问题，我们开发了可诱导的无小鼠模型，以隔离年龄和损伤特定效果，同时避免混淆问题。该提案的总体目标是描述协调的机制，从而改变Decorin和Biglancan表达的改变会影响衰老期间看到的有害影响，以及受伤和修复过程。在肌腱衰老期间，将定义涉及导致损伤反应的SLRP的相互作用。我们的一般假设是，肌腱衰老和年龄相关的肌腱损伤反应受损是SLRP介导的机制的结果。具体而言，Biglancan和Decorin的差分表达的顺序变化提供了重新建立肌腱结构和功能所需的坐标调节相互作用。这些模式因老化而破坏，导致结构，功能和修复能力改变。该研究的目的是：目标1：定义SLRP会影响肌腱衰老的机制。目标2：定义老化改变SLRP在肌腱损伤反应中的调节作用的机制。 AIM 3：确定随着衰老的肌腱损伤反应中添加SLRP的差异效应。我们将利用我们的新型诱导小鼠模型，并利用它们的临时特异性，以系统地定义Decorin和Biglycan在肌腱衰老以及相关的改变损伤反应中的作用。这将与SLRP的全身给药结合起来，以生成四个不同的组成，用于分析机械角色。我们的屈肌肌腱损伤模型以及机械和组织特性的复杂和创新度量以及组成曲线将用于得出对这些响应的机械理解。此外，这些分析将提供对Decorin和Bigylcan在衰老和损伤反应中的调节相互作用的基本理解。最后，这些信息将为这些SLRP的对比和潜在的协同作用提供进一步研究的框架，这将有助于对与年龄相关的肌腱损伤进行改进的治疗方法。