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、成熟和愈合过程中的分层建立是 依赖于 I 型胶原蛋白组装成原纤维和高级结构。调节原纤维形成 胶原蛋白 XI 和 V 对于原纤维组装和纤维组织的调节至关重要，尽管 数量上的次要成分。 XI 型胶原蛋白在发育过程中表达，但在发育过程中几乎不存在 成熟肌腱，而胶原蛋白 V 在整个发育、成熟和成熟肌腱中表达。 在损伤反应期间，XI 型胶原蛋白短暂增加，V 型胶原蛋白持续增加 表达。重要的是，具有 COL11A1 突变的 Stickler 综合征患者的临床表型 COL5A1 伴有典型的埃勒斯丹洛斯综合征，包括涉及肌腱和韧带的关节松弛。还， XI 型胶原蛋白和 V 型胶原蛋白基因与肌腱病有关，而 V 型胶原蛋白基因与 ACL 断裂有关 女性。这些发现支持这些胶原蛋白在建立 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，并且这些机制在受伤后得到重现。 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肌腱的分层组装。这 假设初始肌腱结构和功能的建立需要相互作用 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； （目标 2）阐明涉及胶原蛋白 XI 和/或胶原蛋白 XI/V 的协同作用的调节机制 肌腱对损伤的反应。假设是，调节机制参与了重新获得 肌腱的结构和功能需要协调胶原蛋白 XI 和 XI/V 的表达。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 肌腱的组织及其机械性能。 XI 胶原蛋白会影响损伤的早期阶段 胶原蛋白 XI/V 的协同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型小鼠模型来调节胶原蛋白 XI 和 XI/V 的表达 随后定义了对结构、宏观力学、原纤维力学和 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，提供对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，这些数据将为开发提供重要基础。 未来的治疗干预措施可在疾病状态或受伤后调节这些关键的胶原蛋白。 第1页