Collagen XI and XI/V regulatory mechanisms in assembly of tendon hierarchical structure and acquisition of mechanical properties in development and injury response

胶原蛋白 XI 和 XI/V 在肌腱分层结构组装以及发育和损伤反应中机械性能获取中的调节机制

• 批准号: 10172850
• 负责人: LOUIS J SOSLOWSKY
• 金额: $ 32.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172850
• 关键词: Collagen; Connective Tissue Diseases; Data; Development; Discrimination; Disease; Ehlers-Danlos Syndrome; Female; Fiber; Foundations; Functional disorder; Future; Genes; Higher Order Chromatin Structure; Impairment; Individual; Injury; Joint Laxity; Knock-out; Knockout Mice; Ligaments; Link; Mechanics; Mediating; Minor; Modeling; Mus; Mutation; Pathology; Patients; Property; Regulation; Role; Stickler syndrome; Structure; Tendinopathy; Tendon Injuries; Tendon structure; Therapeutic Intervention; Woman; anterior cruciate ligament rupture; clinical phenotype; healing; interdisciplinary approach; knock-down; male; mechanical properties; mouse model; novel; organizational structure; repaired; response to injury; scleraxis; tendon development; virtual; wound

The hierarchical establishment of tendon structure and function during development, maturation and healing is dependent upon collagen I assembly into fibrils and higher order structures. The regulatory fibril-forming collagens XI and V are essential in the regulation of fibril assembly and fiber organization, despite being quantitatively minor components. Collagen XI is expressed during development, but is virtually absent in mature tendons, while collagen V is expressed throughout development, maturation, and in mature tendon. During the injury response there is a transient increase in collagen XI and sustained increase in collagen V expression. Importantly, the clinical phenotype in patients with mutations in COL11A1 with Stickler's Syndrome and COL5A1 with classic Ehlers Danlos Syndrome includes joint laxity involving tendons and ligaments. Also, collagen XI and V genes are linked to tendinopathy while collagen V genes are linked to ACL rupture in women. These findings support critical regulatory mechanisms for these collagens in the establishment of tendon structure and function, re-establishment after injury, as well as alterations associated with pathologies supporting our general hypothesis that collagen XI- and synergistic collagen XI/V-mediated mechanisms are necessary for establishing tendon structure/function and that these mechanisms are recapitulated after injury. Our specific aims are to: (Aim 1) Define the mechanism(s) involving collagen XI interactions and synergistic collagen XI/V interactions regulating the hierarchical assembly of the tendon required for function. The hypotheses are that establishment of initial tendon structure and function requires interactions involving collagen XI while continued development and maturation require coordinate collagen XI and V interactions; (Aim 2) Elucidate the regulatory mechanism(s) involving collagen XI and/or synergistic roles of collagens XI/V in the tendon response to injury. The hypothesis is that regulatory mechanisms involved in the reacquisition of tendon structure and function require coordinate collagen XI and XI/V expression. Specifically, altering collagen XI or XI/V expression will cause an impairment of repair including fibril assembly, wound matrix organization, and integration of new matrix into the surrounding unwounded matrix influencing structural organization of the tendon and its mechanical properties. Collagen XI will influence the early stages of injury response while synergistic collagen XI/V interactions will have a broad impact in all stages. Our multidisciplinary approach will utilize novel mouse models to modulate collagen XI and XI/V expression followed by a definition of the effects on the structural, macro-scale mechanical, fibril mechanical, and compositional properties. These studies will define tendon-specific regulatory mechanisms involving collagens XI and XI/V, providing a mechanistic understanding of the acquisition of tendon structure and function including its re-establishment in response to injury. Further, the data will provide a critical foundation for developing future therapeutic interventions for modulating these critical collagens in disease states or following injury. Page1

肌腱结构和功能在发育，成熟和治愈过程中的层次结构建立是 取决于胶原蛋白I组装成原纤维和高阶结构。调节原纤维形成 尽管是 定量较小的成分。胶原蛋白XI在开发过程中表达，但实际上不存在 成熟的肌腱，而胶原蛋白V在整个发育，成熟和成熟肌腱中都表达。 在受伤反应期间，胶原蛋白XI的短暂增加和胶原蛋白V的持续增加 表达。重要的是，COL11A1患者患有Stickler综合征的突变患者的临床表型 和经典的Ehlers Danlos综合征的Col5a1包括涉及肌腱和韧带的关节松弛性。还， 胶原蛋白XI和V基因与肌腱病有关，而胶原蛋白V基因与ACL破裂有关 女性。这些发现支持这些胶原蛋白的关键调节机制 肌腱结构和功能，受伤后的重建以及与病理相关的改变 支持我们的一般假设，即胶原蛋白XI-和协同胶原蛋白XI/V介导的机制是 建立肌腱结构/功能所必需的，并在受伤后概括了这些机制。 我们的具体目的是：（目标1）定义涉及胶原蛋白相互作用和协同作用的机制 胶原蛋白XI/V相互作用调节功能所需的肌腱的层次组件。这 假设是建立初始肌腱结构和功能需要涉及的相互作用 胶原蛋白XI在持续的开发和成熟时需要坐标胶原蛋白XI和V相互作用； （AIM 2）阐明涉及胶原蛋白XI和/或胶原蛋白XI/V协同作用的调节机制 在肌腱对损伤的反应中。假设是，涉及重新出发的监管机制 肌腱结构和功能需要坐标胶原蛋白XI和XI/V表达。具体来说，改变 胶原蛋白XI或XI/V表达将导致修复受损，包括原纤维组件，伤口矩阵 组织，以及将新矩阵集成到周围未能影响结构的未质量的矩阵中 肌腱的组织及其机械性能。胶原蛋白XI将影响受伤的早期阶段 响应虽然协同胶原蛋白XI/V相互作用将在各个阶段产生广泛的影响。我们的 多学科方法将利用新颖的鼠标模型来调节胶原蛋白XI和XI/V表达 然后定义对结构，宏观机械，原纤维机械和 组成特性。这些研究将定义涉及胶原蛋白的肌腱特异性调节机制 xi和xi/v，对肌腱结构和功能的获取提供了机械理解 它是为了响应伤害的重新建立。此外，数据将为开发的关键基础 未来的治疗干预措施，用于调节疾病状态或受伤后的这些关键胶原蛋白。 第1页