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: 9764267
• 负责人: LOUIS J SOSLOWSKY
• 金额: $ 33.3万
• 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/9764267
• 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、成熟和愈合过程中的分级建立 依赖于I型胶原组装成纤维和更高级别的结构。调节性原纤维的形成 胶原蛋白XI和V在调节纤维聚集和纤维组织方面是必不可少的，尽管它们是 在数量上是次要的成分。XI胶原蛋白在发育过程中表达，但实际上在 V型胶原在肌腱的发育、成熟和成熟过程中均有表达。 在损伤反应中，XI型胶原短暂增加，V型胶原持续增加 表情。重要的是，STICKLER综合征患者COL11A1突变的临床表型 COL5A1具有典型的Ehler Danlos综合征，包括涉及肌腱和韧带的关节松弛。另外， 胶原XI和V基因与肌腱病有关，而胶原V基因与前交叉韧带断裂有关。 女人。这些发现支持在建立这些胶原蛋白的关键调控机制 肌腱的结构和功能、损伤后的重建以及与病理相关的改变 支持我们的假设，即胶原蛋白XI-和协同胶原蛋白XI/V介导的机制是 这是建立肌腱结构/功能所必需的，这些机制在受伤后重述。 我们的具体目标是：(目标1)确定涉及胶原蛋白XI相互作用和协同作用的机制(S) 胶原蛋白XI/V相互作用调节肌腱功能所需的分层组装。这个 假设初始肌腱结构和功能的建立需要相互作用，包括 胶原蛋白XI的持续发育和成熟需要协调胶原蛋白XI和V的相互作用； (目的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(S) 在肌腱对损伤的反应中。假设是参与重新获得的调节机制 肌腱的结构和功能需要协调胶原XI和XI/V的表达。具体地说，更改 胶原XI或XI/V的表达会导致修复的损害，包括纤维组装、伤口基质 组织新的矩阵，并将其整合到影响结构的周围未受损伤的矩阵中 肌腱的组织及其力学性能。胶原蛋白XI将影响损伤的早期阶段 在反应的同时，胶原蛋白XI/V的协同作用将在所有阶段产生广泛的影响。我们的 多学科方法将利用新的小鼠模型来调节XI和XI/V胶原蛋白的表达 接着定义了对结构、宏观尺度机械、纤维机械和 成分属性。这些研究将确定涉及胶原蛋白的肌腱特异性调节机制 XI和XI/V，提供了对肌腱结构和功能获取的机械理解，包括 它的重建是对伤病的回应。此外，这些数据将为制定 未来的治疗干预措施，用于在疾病状态或受伤后调节这些关键胶原蛋白。 第1页