Rotator Cuff Degeneration and Repair

肩袖退化和修复

• 批准号: 9324527
• 负责人: Leesa M Galatz
• 金额: $ 45.69万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324527
• 关键词: Acute; Affect; Agonist; Animal Model; Bone Regeneration; Chronic; Cicatrix; Clinical; Collagen; Disease; Erinaceidae; Extracellular Matrix; Failure; Fibroblasts; Fibrocartilages; Grant; Head; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Lead; Minerals; Modeling; Muscle; Muscle Cells; NF-kappa B; Natural regeneration; Nuclear; Operative Surgical Procedures; Osteoblasts; Pathology; Pathway interactions; Phase; Plant Roots; Production; Rattus; Rodent Model; Role; Rotator Cuff; Rupture; Signal Transduction; Site; Tendon Injuries; Tendon structure; Testing; Therapeutic; Tissues; Up-Regulation; arm; bone; bone healing; bone loss; clinical care; clinically relevant; cytokine; efficacy testing; healing; improved; inhibitor/antagonist; injury and repair; mechanical properties; mineralization; mouse model; muscle degeneration; novel; patient population; prevent; repaired; response; rotator cuff injury; rotator cuff tear; therapeutic evaluation; tissue repair; treatment strategy

ABSTRACT Chronic degeneration of the rotator cuff leads to tendon tears and poor healing after surgical repair, with failure rates after repair ranging from 20-94%, depending on the patient population. Repair-site rupture is primarily due to poor tendon-to-bone healing: high levels of inflammation lead to fibrovascular scar rather than aligned collagen, and a fibrocartilaginous transition between tendon and bone is not regenerated. Our overall objective is to determine the drivers of degeneration using mouse models and then to test treatment strategies related to these mechanisms in a chronic rat rotator cuff repair model. We have identified two critical features of degeneration and poor healing: inflammation and a lack of fibrocartilage formation. Specifically, there is dramatic upregulation of the NFκB inflammatory pathway during tendon healing and a requirement for hedgehog (Hh) signaling in the formation of fibrocartilage between tendon and bone. Therefore, the current proposal focuses on these two pathways for preventing degeneration and enhancing healing. Specific Aim 1 seeks to determine the role of inflammation, and the NFκB pathway in particular, in rotator cuff degeneration and healing. Inflammation will be modulated genetically in mouse models via the activation and deletion of IKKB, a factor required for NFκB signaling. IKKB will be modulated in tenocytes and muscle cells using inducible Cre models. To test the therapeutic potential of targeting harmful inflammatory cytokines, an IKKB inhibitor will be delivered to rats with repaired chronically degenerated rotator cuffs. Specific Aim 2 will determine role of Hh signaling for fibrocartilage loss during cuff degeneration and fibrocartilage formation during healing. We will first determine the role of Hh signaling for mineral loss at the healing cuff by deleting signaling genetically (via tenocyte- or osteoblast-specific inducible Cre models) or increasing signaling with a Hh agonist. A rat animal model of chronic rotator cuff degeneration followed by repair will then be used to test the efficacy of a Hh agonist for enhanced tendon-to-bone healing.

抽象的 肩袖的慢性退化导致肌腱撕裂，手术修复后愈合不良，最终失败 修复后的比率从 20% 到 94% 不等，具体取决于患者群体。修复部位破裂主要是 由于肌腱到骨骼的愈合不良：高水平的炎症导致纤维血管疤痕而不是对齐 胶原蛋白，肌腱和骨骼之间的纤维软骨过渡不会再生。我们的总体目标 是使用小鼠模型确定退化的驱动因素，然后测试与以下相关的治疗策略 慢性大鼠肩袖修复模型中的这些机制。我们已经确定了两个关键特征 退化和愈合不良：炎症和缺乏纤维软骨形成。具体来说，有 肌腱愈合过程中 NFκB 炎症通路的显着上调以及对 刺猬 (Hh) 信号传导参与肌腱和骨骼之间纤维软骨的形成。因此，当前 该提案重点关注这两种预防退化和促进愈合的途径。具体目标 1 旨在确定炎症，特别是 NFκB 通路在肩袖变性中的作用 和治愈。在小鼠模型中，炎症将通过激活和删除 IKKB，NFκB 信号传导所需的因子。 IKKB 将在肌腱细胞和肌肉细胞中进行调节 诱导型 Cre 模型。为了测试针对有害炎症细胞因子的治疗潜力，IKKB 抑制剂将被输送到修复了慢性退化肩袖的大鼠身上。具体目标 2 将 确定 Hh 信号传导在袖带变性和纤维软骨形成过程中纤维软骨损失的作用 愈合期间。我们将首先通过删除来确定 Hh 信号对于愈合袖口矿物质损失的作用 遗传信号传导（通过肌腱细胞或成骨细胞特异性诱导型 Cre 模型）或通过 呵呵激动剂。然后将使用慢性肩袖退化和修复的大鼠动物模型进行测试 Hh 激动剂增强肌腱至骨愈合的功效。