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

摘录自家长格兰特 肩袖的肩袖疾患在老年人群中尤其具有破坏性，在老年人中泪水是最常见的 50%的60岁以上的人。特定的发育和成熟过程，以及来自机械的线索 加载环境，在整个生命周期中生成和重塑肌腱结构和组成。这些 过程是区域依赖的，这表明了组织的复杂的空间依赖的调节 动态平衡。在老化过程中，正常的成熟过程和机械影响可能导致 亚断裂损伤积聚，最终导致肌腱退变。此应用程序的重点是 确定可能发生这种情况的机制。肌腱结构的发展依赖于 I型胶原蛋白组装成纤维和更高阶的组装。这一过程由相互作用控制，包括 V型胶原是肌腱的一种数量上很小但却很关键的调节成分。最近的研究表明 由于V型胶原含量的减少而改变了纤维/纤维结构，导致对 加载和劣化宏观尺度功能。此外，胶原蛋白对结构有不同的调节作用 V在冈上肌腱的附着点和中质处。这项提议的总体目标是 阐明V型胶原在血管内皮细胞的插入部位和中间物质的不同调节作用(S) 冈上肌腱成熟时和老化过程中。我们的总体假设是，监管 V型胶原的参与随着年龄的增长而变化。这会导致站点特定的监管角色，因为更改的内容和 由于在两个位置存在和组装的基质分子的差异而产生的不同的相互作用。我们 将用靶向V型胶原蛋白的小鼠模型来验证这一假说，这将定义一个异常的作用 基质在衰老中的作用，以及具有新型的V型胶原诱导模型，这将勾勒出改变的作用 V型胶原在肌腱老化过程中的表达具体目标是：目标1：定义场地- 正常情况下结构、成分、动态过程和机械功能的具体变化 冈上肌腱老化。目的2：阐明V型胶原在决定 与年龄相关的冈上肌腱特性下降。目标3：划定特定地点的等级 结构-功能关系作为胶原V含量和衰老的函数利用复杂的多重 回归模型。一种使用靶向和可诱导的小鼠模型的创新方法将定义 V型胶原在衰老过程中的调节作用以及在区域依赖性属性的建立中的作用。这 方法将与复杂和创新的机械(包括疲劳)措施相结合 组织属性，以及组成配置文件，以获得对 管理流程。

Abstract from Parent Grant 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.