Biomechanics and Inflammation in Osteoarthritis

骨关节炎的生物力学和炎症

基本信息

批准号：
8327289
负责人：
Farshid Guilak
金额：
$ 84.02万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8327289
关键词：
Academic Medical Centers Acute Adult Affect Age Analgesics Animal Model Animals Anti-Cytokine Therapy Appearance Arthritis Arthrodesis Arthroplasty Basic Science Behavioral Biochemical Biochemistry Biodistribution Biological Biological Markers Biological Models Biomechanics Biomedical Engineering Body Weight Body Weight decreased Body fat C-reactive protein Cardiovascular system Cartilage Cartilage Matrix Catabolism Cells Characteristics Chondrocytes Clinical Clinical Medicine Clinical Research Clinical Trials Complex Controlled Clinical Trials Coping Skills Core Facility Culture Media Data Degenerative polyarthritis Development Diet Disease Disease Outcome Disease Progression Disuse Atrophy Environmental Risk Factor Enzymes Equilibrium Extracellular Matrix Proteins Family Functional disorder Future Gait Gelatinases Genetic Hand Hemorrhage Human Human Genetics Immobilization In Situ In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-1 Interleukin-6 Interleukins Intervention Investigation Joint Instability Joints Knee Injuries Lead Leukocytes Link Liquid substance Little&apos s Disease Longevity Measures Mechanics Medical Metabolic Metabolism Metalloproteases Modality Modeling Modification Molecular Molecular Biology Muscle Weakness Mutation Nitric Oxide Non-Steroidal Anti-Inflammatory Agents Obesity Older Population Osteotomy Outcome Outcome Measure Outcome Study Overweight Pain Pathogenesis Pathology Patients Pattern Perception Pharmaceutical Preparations Pharmacological Treatment Physical therapy Physiology Pilot Projects Placebo Control Plasma Play Predisposition Prevention Preventive Procedures Process Program Research Project Grants Property Prostaglandin-Endoperoxide Synthase Prostaglandins Protocols documentation Psychosocial Stress Randomized Rattus Reagent Recording of previous events Regulation Renal Blood Flow Replacement Arthroplasty Research Research Activity Research Personnel Research Project Grants Rest Rheumatism Risk Risk Factors Role Serum Source Stress Structure Surgical Management Synovial Fluid Synovial Membrane Synovitis System Testing Therapeutic Tissue Engineering Tissues Training Technics Translating Trauma Tumor Necrosis Factor-alpha United States Weight-Bearing state age related articular cartilage base bone cartilage metabolism clinical application clinical practice cytokine design disability disorder prevention experience flexibility gastrointestinal hazard immunotoxicity in vitro Model in vitro testing in vivo inflammatory marker insight interdisciplinary approach interest joint function joint injury joint loading joint stress kinematics knee pain knowledge translation mortality mouse model novel palliative programs psychologic psychological distress psychosocial receptor research study skills training standardize measure stressor therapy outcome tissue culture trait

项目摘要

DESCRIPTION (provided by applicant): This continuing Program Project focuses on the interaction between biomechanical and inflammatory factors in the pathogenesis of osteoarthritis (OA). The project represents a highly interdisciplinary approach to investigate specific biomechanical, molecular, and psychological mechanisms that relate to disease outcome. The focus of the program is the quantitative study of biomarkers of inflammation, pain, and matrix metabolism in four interrelated studies, performed at the in vivo (human and experimental animal) and in vitro levels. In Project 1, we will examine the influence of genetically- or diet-induced obesity on OA in a mouse model, and examine mechanisms involved in the interaction of biomechanical and biochemical factors on regulating cartilage matrix metabolism and biomarkers of OA using in vitro explant model systems. In Project 2, we will design and evaluate a thermally triggered, in situ forming intra-articular drug depot capable of providing long-term release of anti-cytokine therapies to reduce inflammation and cartilage destruction in a rat joint instability model of OA, as measured by in vitro tests of activity and immunotoxicity, and in vivo tests of biodistribution, and disease-modifying effects. Outcome measures include gross and histological joint appearances, synovial fluid biomarkers, and measures of gait and pain perception. Project 3 represents the continuation of a clinical study to develop more effective physical and psychological interventions to reduce the pain, disability, and psychological distress experienced by overweight patients with persistent OA knee pain. The study evaluates the efficacy of new pain coping skills training and weight reduction protocols on pain, physical disability, and psychological distress using standardized outcome measures of OA pain and function (WOMAC, AIMS, OARSI criteria), biomechanical studies of pain and function, and biomarkers of inflammation and OA. Based on promising pilot study data, Project 4 will involve a randomized placebo controlled clinical trial of IL-1 receptor antagonist (IL-1Ra) for the prevention of pain and chondropathy following acute knee injury. Clinical outcomes will include standardized measures of injury related pain, function and chondropathy (KOOS, IKDC, and SFA score). The Program is supported by two Core facilities. Core A (Administrative Core) will coordinate the administration and research activities of the projects. Core B (Biomarker Core) will serve as a centralized facility for novel reagents, techniques, and training for quantitation of biomarkers of cartilage metabolism and inflammation in tissues and in fluids such as synovial fluid, serum, and tissue culture media. This strategy allows a mechanistic investigation of the overall theme of the project in a manner that can readily be translated from basic science experiments to clinical therapies and outcomes. The information gained from this Program Project will provide new insights into the development new pharmacologic, psychological, and physical therapies for the treatment of OA.

描述（由申请人提供）：该持续计划项目重点关注骨关节炎（OA）发病机制中生物力学和炎症因子之间的相互作用。该项目代表了一种高度跨学科的方法，用于研究与疾病结果相关的特定生物力学、分子和心理机制。该计划的重点是在体内（人类和实验动物）和体外水平进行的四项相关研究中对炎症、疼痛和基质代谢的生物标志物进行定量研究。在项目1中，我们将在小鼠模型中研究遗传或饮食诱导的肥胖对OA的影响，并使用体外外植体模型研究生物力学和生化因素相互作用对调节软骨基质代谢和OA生物标志物的机制。系统。在项目 2 中，我们将设计和评估一种热触发、原位形成的关节内药物储存库，能够提供长期释放的抗细胞因子疗法，以减少 OA 大鼠关节不稳定性模型中的炎症和软骨破坏（如测量）通过活性和免疫毒性的体外测试，以及生物分布和疾病缓解效果的体内测试。结果测量包括关节外观和组织学外观、滑液生物标志物以及步态和疼痛感知的测量。项目 3 代表了一项临床研究的继续，旨在开发更有效的身体和心理干预措施，以减轻患有持续性 OA 膝关节疼痛的超重患者所经历的疼痛、残疾和心理困扰。该研究使用 OA 疼痛和功能的标准化结果测量（WOMAC、AIMS、OARSI 标准）、疼痛和功能的生物力学研究以及炎症和 OA 的生物标志物。基于有希望的试点研究数据，项目 4 将涉及一项 IL-1 受体拮抗剂 (IL-1Ra) 的随机安慰剂对照临床试验，用于预防急性膝损伤后的疼痛和软骨病。临床结果将包括损伤相关疼痛、功能和软骨病的标准化测量（KOOS、IKDC 和 SFA 评分）。该计划由两个核心设施支持。核心A（行政核心）将协调项目的管理和研究活动。 Core B（生物标记核心）将作为新试剂、技术和培训的集中设施，用于定量组织和滑液、血清和组织培养基等液体中的软骨代谢和炎症的生物标记物。该策略允许以一种可以轻松从基础科学实验转化为临床治疗和结果的方式对项目的总体主题进行机械研究。从该计划项目中获得的信息将为开发治疗 OA 的新药理学、心理和物理疗法提供新的见解。