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: 10403332
• 负责人: LOUIS J SOSLOWSKY
• 金额: $ 11.41万
• 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/10403332
• 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是 依赖于胶原I组装成原纤维和更高级的结构。调节性纤维形成 胶原蛋白XI和V对于调节原纤维组装和纤维组织至关重要，尽管它们是 数量较少的成分。胶原蛋白XI在发育过程中表达，但在发育过程中几乎不存在。 成熟肌腱，而胶原V在整个发育、成熟和成熟肌腱中表达。 在损伤反应期间，存在胶原XI的瞬时增加和胶原V的持续增加 表情重要的是，在Stickler综合征患者中，COL 11 A1突变的临床表型 和COL 5A 1与经典的EhlersDanlos综合征包括关节松弛涉及肌腱和韧带。还有， 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断裂有关， 妇女这些发现支持了这些胶原蛋白在建立血管内皮细胞中的关键调节机制。 肌腱结构和功能，损伤后重建，以及与病理相关的变化 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 这是建立肌腱结构/功能所必需的，并且这些机制在损伤后会重演。 我们的具体目标是：（目标1）定义涉及胶原蛋白XI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分级组装。的 假设是，初始肌腱结构和功能的建立需要相互作用， 胶原蛋白XI，而持续的发育和成熟需要协调的胶原蛋白XI和V相互作用; (Aim 2）阐明涉及胶原XI的调节机制和/或胶原XI/V的协同作用 肌腱对损伤的反应。这一假设是，参与重新获得的调节机制 肌腱结构和功能需要协调胶原XI和XI/V表达。具体来说，改变 胶原XI或XI/V表达将导致修复受损，包括原纤维组装、伤口基质 组织，并将新矩阵整合到周围未受伤的矩阵中，影响结构 组织的肌腱和它的机械性能。胶原蛋白XI将影响损伤的早期阶段 而协同胶原XI/V相互作用将在所有阶段产生广泛影响。我们 多学科方法将利用新型小鼠模型来调节胶原蛋白XI和XI/V表达 其次是对结构，宏观尺度机械，原纤维机械， 组成性质这些研究将明确涉及胶原蛋白的肌腱特异性调节机制 XI和XI/V，提供肌腱结构和功能获取的机械理解，包括 它的重建是为了应对伤害。此外，这些数据将为开发 未来的治疗干预，用于调节疾病状态或损伤后的这些关键胶原蛋白。 Page1