Establishing Treatments and Diagnostic Tools for Post-Traumatic OA in Vivo

在体内建立创伤后 OA 的治疗方法和诊断工具

• 批准号: 9133275
• 负责人: Douglas Ray Pedersen
• 金额: $ 34.78万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9133275
• 关键词: Acute; Animal Model; Animals; Ankle; Apoptotic; Arthritis; Basic Science; Cartilage; Cartilage injury; Cell Death; Cessation of life; Chondrocytes; Chronic; Clinical; Clinical Research; Data; Degenerative polyarthritis; Development; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Early identification; Experimental Models; Fracture; Goals; Goat; Healed; Health; Hour; Human; Inflammatory; Inflammatory Response; Injury; Intervention; Joints; Knee; Knee joint; Laboratories; Lead; Magnetic Resonance Imaging; Measures; Mechanical Stress; Mechanics; Mediating; Metabolic; Methods; Modeling; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Necrosis; Operative Surgical Procedures; Organ; Orthopedics; Oryctolagus cuniculus; Outcome; Outcome Study; Pathogenesis; Patients; Pharmacologic Substance; Phase; Process; Production; Residual state; Risk; Severities; Site; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Translational Research; Work; articular cartilage; clinical application; design; effective therapy; healing; high risk; imaging biomarker; improved; in vivo; injured; innovation; interest; joint injury; minimally invasive; molecular marker; novel; novel diagnostics; pre-clinical; prevent; tool; treatment strategy

This project is designed to establish novel treatments to decrease the risk of PTOA, and to investigate new diagnostic tools to identify patients at high risk of PTOA. The goal is to provide effective immediate preclinical information to support clinical application of these treatments and diagnostic tools. The treatments of interest are: 1) cytoprotective treatment that prevents immediate necrotic and acute apoptotic chondrocyte death at/near a site of acute cartilage injury, and 2) chondrocyte metabolic enhancement treatment developed to improve chondrocyte energy production, to restore anabolic function, and to suppress catabolic activities, by modulating the injury-related acute inflammatory response. These treatments will be piloted using a survival rabbit model. In this model, after controlled surgical insults that replicate major factors contributing to pathogenesis of human PTOA following joint injuries (i.e., acute joint injury and excessive cumulative mechanical stress to the injured cartilage), progressive cartilage loss predictably develops in the experimental joints (knees) in a relatively short period (8 weeks). Using this animal model of rapid-progression PTOA, work is proposed to test if the above treatments are capable of mitigating the early biologically mediated disease process of PTOA in vivo, and whether the treatments effectively decrease subsequent cartilage loss. The diagnostic tools of interest are: 1) MR imaging that visualizes/measures inflammatory anatomical changes and early intra-cartilage degenerative changes prior to cartilage loss, and 2) molecular biomarker analysis that measures whole-joint inflammation and whole-joint cartilage metabolic activity. The diagnostic power of these clinically applicable non- or minimally-invasive tools will be tested in a goat survival model of acute cartilage injury (created by means of precisely controlled blunt impaction insult). Work is proposed to test if these tools are capable of characterizing the severity of acute joint injury in vivo (particularly focusing on cartilage damage), and to test if subsequent progression of cartilage loss in these joints is reliably predictable using the early (< 1 month) information provided by these diagnostic tools.

该项目旨在建立新的治疗方法来降低 PTOA 风险，并研究新的诊断工具来识别 PTOA 高风险患者。目标是提供有效的即时临床前信息，以支持这些治疗和诊断工具的临床应用。感兴趣的治疗方法是：1）细胞保护治疗，防止急性软骨损伤部位/附近立即坏死和急性凋亡软骨细胞死亡，2）软骨细胞代谢增强治疗，通过调节损伤相关的急性炎症反应，改善软骨细胞能量产生，恢复合成代谢功能，并抑制分解代谢活动。这些治疗方法将使用存活兔子模型进行试点。在该模型中，在复制了关节损伤后导致人类 PTOA 发病机制的主要因素（即急性关节损伤和受伤软骨过度累积机械应力）的受控手术损伤后，可预见的是，在相对较短的时间内（8 周），实验关节（膝盖）会出现渐进性软骨损失。使用这种快速进展的 PTOA 动物模型，建议开展工作来测试上述治疗是否能够减轻体内 PTOA 的早期生物介导的疾病过程，以及这些治疗是否有效减少随后的软骨损失。 感兴趣的诊断工具是：1) MR 成像，可可视化/测量软骨损失之前的炎症解剖变化和早期软骨内退行性变化，2) 分子生物标志物分析，可测量全关节炎症和全关节软骨代谢活动。这些临床适用的非或微创工具的诊断能力将在急性软骨损伤的山羊生存模型（通过精确控制的钝性撞击损伤产生）中进行测试。建议开展工作来测试这些工具是否能够表征体内急性关节损伤的严重程度（特别是软骨损伤），并测试使用这些诊断工具提供的早期（< 1 个月）信息是否可以可靠地预测这些关节中软骨损失的后续进展。