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

 描述(申请人提供)：肌腱损伤是一个常见的问题，在老龄化的人口中加剧。严重的疼痛和残疾与这些伤害有关，导致生活质量下降、失去工作和独立。富含亮氨酸的小分子蛋白多糖(SLRPs)与其他基质分子的相互作用对肌腱的分级组装以及肌腱机械功能的建立或重建具有重要的调控作用。I类SLRPs，核心蛋白和Biglycan，在生长、衰老和损伤反应中表现出表达的变化。核心蛋白聚糖的缺失改善了与衰老相关的力学和纤维参数的变化，并且不利于肌腱损伤的反应。这些数据表明SLRPs在肌腱中起着关键的调节作用。不幸的是，这一领域的进展受到现有模型系统的限制。使用传统的基因敲除小鼠不能控制时间或空间的特异性，继发性和代偿性效应也无法控制。为了解决这个问题，我们开发了可诱导的空小鼠模型，以分离年龄和损伤的特定影响，同时避免混淆的问题。这项提案的总体目标是描述核心蛋白和大聚糖表达的变化影响衰老过程中以及损伤和修复过程中的有害影响的协调机制。在肌腱老化过程中，将定义导致损伤反应受损的SLRP的相互作用。我们的一般假设是，肌腱老化和肌腱损伤的年龄相关反应受损是相似的SLRP介导机制的结果。具体地说，Biglycan和Decorin差异表达的顺序变化提供了重建肌腱结构和功能所需的协调调控相互作用。随着年龄的增长，这些模式被打乱，导致结构、功能和修复能力的改变。本研究的目的是：目的1：明确SLRPs影响肌腱老化的机制。目的2：明确衰老改变肌腱损伤反应中SLRPs调节作用的机制(S)。目的：测定SLRPS对增龄肌腱损伤反应的差异性效应(S)。我们将利用我们的新的可诱导小鼠模型，并利用它们的时间特异性来系统地确定核心蛋白聚糖和双聚糖在肌腱老化和相关的损伤反应改变中的作用。这将与SLRP的系统管理相结合，以产生四个不同的组合，用于分析机械性作用。我们的屈肌腱损伤模型结合复杂和创新的力学和组织特性测量方法，以及成分分布，将用于从机制上对这些反应进行理解。此外，这些分析将提供对核心蛋白和二聚糖在衰老和损伤反应中的调节相互作用的基本理解。最后，这些信息将为进一步研究这些SLRP的对比和潜在的协同作用提供一个框架，这将有助于设计改进的年龄相关性肌腱损伤的治疗方法。

 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.