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: 8539464
• 负责人: Douglas Ray Pedersen
• 金额: $ 35.02万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539464
• 关键词: Acute; Animal Model; Animals; Ankle; Apoptotic; Arthritis; Basic Science; Biological Markers; 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; Molecular; 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; Relative (related person); 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; improved; in vivo; injured; innovation; interest; joint injury; minimally invasive; 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的风险，并研究新的诊断工具来识别PTOA的高危患者。其目标是提供有效的、即时的临床前信息，以支持这些治疗和诊断工具的临床应用。有兴趣的治疗包括：1)细胞保护治疗，防止急性软骨损伤部位/附近的软骨细胞立即坏死和急性凋亡死亡；2)软骨细胞代谢增强治疗，通过调节与损伤相关的急性炎症反应，改善软骨细胞的能量产生，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的兔子模型进行试验。在这个模型中，在有控制的手术损伤后，复制了导致关节损伤后人类PTOA发病的主要因素(即急性关节损伤和损伤软骨的过度累积机械应力)，在相对较短的时间(8周)内，实验关节(膝关节)可预测地发生进行性软骨丢失。利用这种快速进展的PTOA动物模型，我们建议测试上述治疗方法是否能够缓解体内早期的生物介导性PTOA的疾病过程，以及这些治疗方法是否有效地减少随后的软骨丢失。 值得注意的诊断工具包括：1)MR成像，用于可视化/测量软骨丢失前的炎性解剖变化和早期软骨内退行性变化；2)分子生物标记物分析，用于测量全关节炎症和全关节软骨代谢活动。这些临床上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存活模型中进行测试(通过精确控制的钝化撞击产生)。有人建议测试这些工具是否能够在体内表征急性关节损伤的严重程度(特别是软骨损伤)，并使用这些诊断工具提供的早期(1个月)信息来测试这些关节软骨随后的进展是否可以可靠地预测。