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.

肩关节的肩袖疾病在老年人群中尤其具有破坏性， 50%的人超过60岁。特定的发育和成熟过程，沿着来自机械 加载环境，生成和重塑整个生命周期的肌腱结构和组成。这些 过程是区域依赖性的，表明组织的复杂的空间依赖性调节 体内平衡在老化过程中，正常的成熟过程和机械影响可导致 亚断裂损伤的累积，最终导致肌腱退化。此应用程序的重点是 确定可能发生这种情况的机制。肌腱结构的发育取决于 胶原蛋白I组装成原纤维和更高级的组装体。这个过程是由相互作用控制的， 胶原V，一种数量上较小但对肌腱起关键调节作用的成分。最近的研究表明 由于胶原蛋白V含量降低而改变的原纤维/纤维结构导致了对 负载和宏观功能较差。此外，胶原蛋白对结构有不同的调节作用， V在冈上肌腱的插入部位和中间物质。本建议的总体目标是 为了阐明胶原V在插入位点和中间物质的差异调节作用， 冈上肌腱在成熟和老化过程中。我们的一般假设是， 包括胶原蛋白V随着年龄的增长而变化。这导致由于改变的内容而产生位点特异性调节作用， 不同的相互作用导致的基质分子的差异存在和组装在两个网站。我们 将使用靶向胶原V小鼠模型来测试这一假设，这将定义异常胶原蛋白的作用。 基质在衰老中的作用，以及新的胶原V诱导模型，这将描绘改变的作用。 胶原V在肌腱老化过程中的表达。具体目标是：目标1：确定场地- 正常情况下的结构、组成、动态过程和机械功能的特定变化 冈上肌腱老化。目的2：阐明胶原V在决定细胞凋亡中的位点特异性差异作用 冈上肌腱性能的老化相关下降。目标3：划定特定地点的等级 结构-功能关系作为胶原V含量和老化的函数，利用复杂的多重 回归模型使用靶向和诱导型小鼠模型的创新方法将定义 胶原V在老化过程中的调节作用，并在建立区域依赖性的属性。这 方法将与机械（包括疲劳）和 组织特性，以及组成概况，以获得对 治理过程。