Qualification of Prognostic and Diagnostic Biomarkers of Knee Osteoarthritis

膝骨关节炎的预后和诊断生物标志物的鉴定

• 批准号: 9289779
• 负责人: Virginia Kraus
• 金额: $ 68.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9289779
• 关键词: African American; Age; Analgesics; Appearance; Biochemical; Biochemical Markers; Biological Markers; Blood Tests; Body mass index; Caucasians; Clinical; Clinical Trials; County; Degenerative polyarthritis; Diagnosis; Diagnostic; Diagnostic radiologic examination; Early identification; Early treatment; Enzyme-Linked Immunosorbent Assay; Evaluation; Failure; Female; Foundations; Future; Goals; Hand; Hip region structure; Image; Individual; Inflammatory; Joints; Kellgren-Lawrence grade; Knee; Knee Osteoarthritis; Knee joint; Magnetic Resonance Imaging; Measures; Modeling; Modification; Pain; Pathologic Processes; Patients; Peptides; Persistent pain; Pharmaceutical Preparations; Phenotype; Prognostic Marker; Proteins; Proteomics; Race; Reporting; Risk; Sampling; Serum; Symptoms; Synovial Fluid; Testing; United States Food and Drug Administration; United States National Institutes of Health; Urine; Vertebral column; Width; Woman; Work; base; biomarker panel; candidate marker; clinical predictors; clinically relevant; cohort; combinatorial; cost; design; diagnostic biomarker; drug development; follow-up; high risk; improved; interest; joint injury; knee pain; men; multiple reaction monitoring; predictive marker; secondary outcome; sex; success; tool; tool development

Abstract A cure for osteoarthritis (OA) remains elusive. This is due in large part to two major obstacles, inability to detect OA sufficiently early before the onset of irreversible signs and recalcitrant symptoms, and inability to identify individuals at high risk of progression based on traditionally used metrics (age, sex, body mass index, knee pain and joint space width). The latter challenge is responsible for low powering of clinical trials and numerous drug trial failures. Using a systematic, unbiased and iterative approach, we have created a multiple reaction monitoring (MRM) proteomic panel for serum-based prediction of knee OA structural progression and diagnosis of knee OA. The selection of proteins was based on results of extensive discovery proteomic studies in synovial fluid, urine, and serum from knee OA radiographic progressors and non-progressors (with 3-4 year follow-up) and controls. The ultimate goals of this work are to qualify these new biomarker candidates in the contexts of knee OA progression and OA diagnosis in larger well-phenotyped cohorts from the Osteoarthritis Initiative, the Johnston County Osteoarthritis Project and the Chingford cohorts. With this further qualification, these new biomarker tools will be very significant for their potential utility for clinical trial and clinical use to inform strategies for phenotyping and earlier identification and treatment of OA patients. We also intend to pursue formal Food and Drug Administration (FDA) qualification of the optimal marker set yielded by this proposal to facilitate their use as drug development tools.

摘要 骨关节炎（OA）的治疗仍然难以捉摸。这在很大程度上是由于两个主要障碍， 在不可逆体征和顽固性症状发作之前足够早地检测OA， 基于传统使用的指标（年龄，性别，体重指数， 膝关节疼痛和关节间隙宽度）。后一个挑战是导致临床试验效力低的原因， 多次药物试验失败。使用系统的，无偏见的和迭代的方法，我们已经创建了一个多个 用于基于血清预测膝关节OA结构进展的反应监测（MRM）蛋白质组学面板， 膝关节OA的诊断。蛋白质的选择是基于广泛的发现蛋白质组学研究的结果 在膝关节OA放射学进展者和非进展者（3-4年）滑液、尿液和血清中 跟踪）和控制。这项工作的最终目标是使这些新的生物标志物候选物在临床上合格。 膝关节OA进展和OA诊断的背景，来自骨关节炎的较大的良好表型队列 倡议，约翰斯顿县骨关节炎项目和清福德队列。有了这个进一步的限定， 这些新的生物标志物工具对于临床试验和临床应用的潜在效用将是非常重要的， 为OA患者的表型分型和早期识别和治疗提供信息策略。我们还打算 寻求正式的食品和药物管理局（FDA）的最佳标志物集的资格， 建议促进将其用作药物开发工具。