Project 2: Synovial Fluid Proteomics

项目2：滑液蛋白质组学

• 批准号: 10555687
• 负责人: DAVID Tobin FELSON
• 金额: $ 84.62万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555687
• 关键词: Arthralgia; Arthritis; Biological Assay; Biological Markers; Biology; Biomechanics; Blood; Cartilage; Degenerative polyarthritis; Development; Disease; Disease Progression; Functional disorder; Goals; Hand; Hand Osteoarthritis; Incidence; Individual; International; Joints; Knee; Knee Osteoarthritis; Knowledge; Magnetic Resonance Imaging; Measures; Mechanics; Molecular; Molecular Profiling; Outcome; Pain; Participant; Pathogenesis; Pathogenicity; Pharmacological Treatment; Plasma; Plasma Proteins; Process; Prospective cohort; Proteins; Proteome; Proteomics; Research Design; Risk Assessment; Risk Factors; Sampling; Site; Synovial Fluid; Tissues; United States; Visit; aged; aptamer; biomarker identification; cohort; cost; early detection biomarkers; insight; knee pain; novel; novel marker; novel therapeutic intervention; osteoarthritis pain; physically handicapped; progression risk; proteomic signature; radiological imaging; success; ultrasound

ABSTRACT Project 2: Synovial Fluid Proteomics (previously Project 4) Osteoarthritis (OA) is the most common form of arthritis and a leading cause of physical disability in older individuals. There are no approved pharmacologic treatments available beyond those for symptomatic relief and no biomarkers available to assess disease status or risk of progression. Major reasons for this may include key differences between blood and intra-articular biomarkers and the dominating influence of biomechanics that makes it difficult to differentiate systemic from mechanical contributions to OA. There may be differences between single-site knee and multi-site OA that occurs in hands and knees since the latter may result from systemic initiation rather than joint-specific factors. Assessment of proteins in joint-specific synovial fluid that is in direct contact with joint tissues and paired blood plasma may provide insights into joint-specific and systemic factors in OA. The proposed study will fill a gap in knowledge about the pathobiology of knee and multi-site OA. The objective of this proposal is to identify novel OA biology underlying knee and multi-site OA using proteomic analyses of paired synovial fluid and blood plasma. Our central hypothesis is that there are molecular signatures in synovial fluid and blood plasma that can be used to identify biomarkers for OA and which differentiate systemic from joint-specific molecular contributors to OA. Our long-term goal is to identify biomarkers that assess OA burden and disease progression and that provide insights into disease pathogenesis. We will assess returning participants from the Multicenter Osteoarthritis Study (MOST), a well-characterized prospective cohort of older individuals aged 54-86 years to assess risk factors for incidence and progression of knee OA. All participants will undergo radiographic assessments for hand and knee OA at MOST4 Visit 1. Synovial fluid will be collected in those who have at least 1 ml of synovial fluid present on knee ultrasound (~500 participants), which will include those with and without frequent knee pain. We will measure proteins in ~500 paired synovial fluid and blood plasma samples using SOMAScan, an aptamer-based proteomics assay that simultaneously detects ~7,000 proteins. Proteomic findings in MOST will be replicated in an international consortium, STEpUP OA, which includes ~1,800 individuals from 5 cohorts with proteomic profiling in synovial fluid and plasma. Aim 1 will identify proteins in knee OA synovial fluid and plasma associated cross-sectionally with knee pain and MRI-detected cartilage damage. Aim 2 will identify proteins in knee OA synovial fluid and plasma associated with longitudinal worsening of knee pain or MRI-detected cartilage damage over 24 months. Aim 3 will identify proteins in plasma associated with multi-site OA. The expected outcome of this proposal is identification of proteomic signatures that underlie OA pathogenesis. This will be the first and largest study of paired OA synovial fluid and plasma proteomics, which will likely provide novel insights into joint-specific and systemic contributions to OA pathophysiology needed to identify novel biomarkers and suggest new treatment strategies for OA.

摘要项目2：滑液蛋白质组学（先前项目4） 骨关节炎（OA）是关节炎的最常见形式，是老年人的身体残疾的主要原因 个人。除症状缓解外，没有批准的药理治疗可用 没有可用于评估疾病状况或进展风险的生物标志物。这样做的主要原因可能包括密钥 血液和关节内生物标志物之间的差异以及生物力学的主导影响 很难将系统性与机械贡献区分开。可能有差异 在单位膝盖和多站点OA之间发生在手和膝盖之间，因为后者可能是由 全身性启动而不是特定因素。评估联合特异性滑液中蛋白质的评估 直接与关节组织和配对的血浆接触可能会提供有关联合特异性和全身性的见解 OA中的因素。拟议的研究将填补有关膝盖和多站点OA病理生物学的知识的空白。 该建议的目的是使用蛋白质组学识别膝盖和多站点OA的新型OA生物学 分析配对的滑液和血浆。我们的中心假设是有分子特征 在滑液和血浆中，可用于识别OA的生物标志物，并且可以区分全身性 从联合特异性分子贡献者到OA。我们的长期目标是确定评估OA的生物标志物 负担和疾病进展，并提供了对疾病发病机理的见解。我们将评估返回 多中心骨关节炎研究（大多数）的参与者，这是一个充分表现的前瞻性队列 54-86岁的个人评估膝盖OA发病率和进展的危险因素。所有参与者 将对手和膝盖OA进行放射线照相评估，最多4次访问1。滑液将收集 在膝盖超声（约500名参与者）上至少有1毫升滑液的人中，其中包括 那些没有膝盖疼痛的人。我们将在约500个配对的滑液和血液中测量蛋白质 使用SOMASCAN的等离子体样品，Somascan，一种基于适体的蛋白质组学测定法，同时检测约7,000 蛋白质。大多数蛋白质组学的发现将在国际财团中复制 包括来自5个同类群的约1,800个个体，具有滑液和血浆中的蛋白质组学分析。 AIM 1将确定 膝关节液和膝关节疼痛的横截面和MRI检测的蛋白质中的蛋白质 软骨伤害。 AIM 2将识别与纵向相关的膝关节流体和血浆中的蛋白质 在24个月内，膝盖疼痛或MRI检测的软骨损伤恶化。 AIM 3将识别等离子体中的蛋白质 与多站点OA相关。该提案的预期结果是识别蛋白质组学特征 这是OA发病机理的基础。这将是对OA滑液和等离子体配对的第一项也是最大的研究 蛋白质组学可能会提供对OA的联合特异性和系统贡献的新见解 需要病理生理学来识别新型生物标志物并为OA提出新的治疗策略。