Rotator Cuff Degeneration and Repair

肩袖退化和修复

• 批准号: 9770546
• 负责人: Leesa M Galatz
• 金额: $ 43.01万
• 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/9770546
• 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.

摘要 肩袖的慢性变性导致肌腱撕裂，手术修复后愈合不良， 根据患者人群，修复后的比率范围为20- 94%。修复部位破裂主要是 由于腱-骨愈合不良：高度炎症导致纤维血管瘢痕，而不是对齐 胶原，并且肌腱和骨之间的纤维软骨过渡不能再生。我们的整体目标 是使用小鼠模型确定退化的驱动因素，然后测试与 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， 在肌腱愈合过程中NFκB炎症通路的显著上调， Hedgehog（Hh）信号在肌腱和骨之间纤维软骨形成中的作用。因此目前 该提案的重点是这两个途径，以防止退化和促进愈合。具体目标1 旨在确定炎症的作用，特别是NFκB通路，在肩袖退变中的作用 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将在腱细胞和肌肉细胞中被调节， 诱导型Cre模型。为了测试靶向有害炎症细胞因子的治疗潜力， 将抑制剂递送至具有修复的慢性退化肩袖的大鼠。具体目标2将 确定Hh信号在袖状退变和纤维软骨形成过程中纤维软骨损失中的作用 在愈合过程中。我们将首先确定Hh信号传导在愈合袖带矿物质损失中的作用， 遗传信号传导（通过腱细胞或成骨细胞特异性诱导型Cre模型）或增加信号传导， Hh激动剂。然后，将使用慢性肩袖退化的大鼠动物模型进行修复，以测试 Hh激动剂对增强腱-骨愈合的功效。