Differential Roles of Collagen V in Establishing the Regional Properties in Mature and Aging Supraspinatus Tendons

V 型胶原蛋白在建立成熟和老化冈上肌腱区域特性中的不同作用

• 批准号: 9215094
• 负责人: DAVID E BIRK
• 金额: $ 35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215094
• 关键词: Aging; Aging-Related Process; Collagen; Complex; Coupled; Cues; Development; Disease; Environment; Fatigue; Fiber; Homeostasis; Inferior; Leucine; Life; Measures; Mechanics; Minor; Modeling; Morphology; Mus; Premature aging syndrome; Process; Property; Proteoglycan; Recovery; Regulation; Role; Rotator Cuff; Rupture; Shoulder; Site; Slide; Structure; Structure-Activity Relationship; Tendon structure; Testing; Tissues; age related; aged; aging population; fibrillogenesis; innovation; mechanical load; mechanical properties; mouse model; novel; response; supraspinatus muscle; tendon development

Rotator cuff disorders of the shoulder are particularly devastating in the aging population with tears present in 50% of people over 60. Specific development and maturation processes, along with cues from the mechanical loading environment, generate and remodel tendon structure and composition throughout life. These processes are regionally-dependent, suggesting a complex spatially-dependent regulation of tissue homeostasis. During aging, normal maturation processes and mechanical influences can result in accumulation of sub-rupture damage and ultimately to tendon degeneration. The focus of this application is to determine the mechanisms by which this might occur. The development of tendon structure is dependent upon collagen I assembly into fibrils and higher order assemblies. This process is controlled by interactions involving collagen V, a quantitatively minor yet critical regulatory component of tendon. Recent studies demonstrated that altered fibril/fiber structure due to decreased collagen V content results in an inferior dynamic response to load and inferior macroscale function. Furthermore, there was a differential regulation of structure by collagen V at the insertion site and midsubstance of the supraspinatus tendon. The overall objective of this proposal is to elucidate the differential regulatory role(s) of collagen V at the insertion site and midsubstance of the supraspinatus tendon both at maturity and during the aging process. Our general hypothesis is that regulation involving collagen V changes with aging. This results in site-specific regulatory roles due to altered content and distinct interactions resulting from differences in matrix molecules present and assembled at the two sites. We will test this hypothesis using targeted collagen V mouse models, which will define the role of an abnormal matrix in aging, as well as with novel collagen V inducible models, which will delineate the role of altered collagen V expression in the progression of tendon aging. The specific aims are to: Aim 1: Define the site- specific alterations in structure, composition, dynamic processes and mechanical function during normal supraspinatus tendon aging. Aim 2: Elucidate the site-specific differential roles of collagen V in determining aging-associated declines in supraspinatus tendon properties. Aim 3: Delineate site-specific hierarchical structure-function relationships as a function of collagen V content and aging utilizing sophisticated multiple regression models. An innovative approach using targeted and inducible mouse models will define the regulatory roles of collagen V during aging and in the establishment of regionally-dependent properties. This approach will be coupled with sophisticated and innovative measures of mechanical (including fatigue) and organizational properties, together with compositional profiles, to derive a mechanistic understanding of the governing processes.

肩膀的肩袖疾病在老龄化的人口中尤其是毁灭性的，流泪 60岁以上的人中有50％。具体的发展和成熟过程，以及机械的提示 加载环境，生成和重塑肌腱结构和整个生命。这些 过程是区域依赖性的，表明对组织的复杂依赖性调节 稳态。在衰老期间，正常的成熟过程和机械影响可能导致 累积亚爆炸损伤，最终导致肌腱变性。该应用的重点是 确定可能发生这种情况的机制。肌腱结构的发展取决于 胶原蛋白I组装成原纤维和高阶组件。此过程由涉及的互动控制 胶原蛋白V，肌腱的定量较小但关键的调节成分。最近的研究表明 由于胶原蛋白V含量减少而导致的原纤维/纤维结构改变了对 负载和下宏观功能。此外，通过胶原蛋白对结构有差异调节 v在上张肌腱的插入部位和中缩。该提议的总体目标是 阐明胶原蛋白V的差异调节作用 上张肌腱在成熟度和衰老过程中。我们的总体假设是调节 涉及胶原蛋白V随老化的变化。这导致由于内容改变而导致特定地点的调节作用 由于存在和组装在两个位点的基质分子的差异而产生的不同相互作用。我们 将使用有针对性的胶原蛋白V小鼠模型检验该假设，该模型将定义异常的作用 衰老中的矩阵以及新型胶原蛋白V诱导模型，该模型将描述改变的作用 肌腱衰老进展中的胶原蛋白V表达。具体目的是：目标1：定义站点 - 正常情况下结构，组成，动态过程和机械功能的特定变化 肌腱衰老。目标2：阐明胶原蛋白V的位点特异性差分作用 衰老相关的肌腱特性下降。目标3：描述特定地点的层次结构 结构功能关系是胶原蛋白V含量的函数和使用复杂多重的老化 回归模型。使用靶向鼠标模型的创新方法将定义 胶原蛋白V在老化和建立区域依赖性特性中的调节作用。这 方法将与机械的精致和创新的衡量（包括疲劳）和 组织属性以及组成概况，以获得对机械的理解 管理过程。