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(以前的项目4) 骨关节炎(OA)是最常见的关节炎形式，也是老年人身体残疾的主要原因 个人。除了缓解症状和治疗外，尚无经批准的药物治疗方法 没有生物标志物可用于评估疾病状态或进展风险。主要原因可能包括以下关键因素 血液和关节内生物标记物的差异及其生物力学的主导影响 这使得很难区分系统性和机械性对骨关节炎的贡献。可能会有不同 发生在手部和膝部的单部位膝骨关节炎和多部位骨关节炎，因为后者可能是 系统性启动，而不是关节特有的因素。关节特异性滑液中蛋白质的检测 直接接触关节组织和配对血浆可能提供对关节特异性和系统性的洞察 影响骨性关节炎的因素。这项拟议的研究将填补关于膝关节和多部位骨关节炎的病理生物学知识的空白。 本研究的目的是利用蛋白质组学方法鉴定膝关节和多部位骨关节炎的新生物学。 滑液和血浆配对分析。我们的中心假设是有分子签名 在滑液和血浆中，可以用来识别OA的生物标志物，并区分系统性 从关节特定的分子贡献者到骨关节炎。我们的长期目标是确定评估骨性关节炎的生物标记物 负担和疾病进展，并提供了对疾病发病机制的洞察。我们将评估返乡情况 来自多中心骨关节炎研究(MOST)的参与者，这是一个具有良好特征的老年前瞻性队列 年龄54-86岁的个体评估膝骨性关节炎的发生和进展的危险因素。所有参与者 将在MOST4会诊1接受手部和膝盖骨关节炎的X光检查。将收集滑液 对于那些膝关节超声检查中至少有1毫升滑液的患者(约500名参与者)，这将包括 那些有和没有频繁膝盖疼痛的人。我们将检测500对滑液和血液中的蛋白质 使用SOMAScan的血浆样本，这是一种基于适体的蛋白质组学分析方法，可以同时检测~7000个 蛋白质。MOST中的蛋白质组发现将在一个名为Stepup OA的国际财团中复制，该财团 包括来自5个队列的约1,800人，他们在滑液和血浆中进行蛋白质组学分析。目标1将确定 膝关节骨性关节炎滑液和血浆中的蛋白质与膝关节疼痛和MRI检测的横断面相关 软骨受损。AIM 2将鉴定膝骨性关节炎滑液和血浆中与纵向相关的蛋白质 膝关节疼痛加重或核磁共振检测到的软骨损伤超过24个月。AIM 3将识别血浆中的蛋白质 与多站点办公自动化相关。这项提议的预期结果是鉴定蛋白质组签名。 这是骨性关节炎发病机制的基础。这将是第一次也是最大规模的配对骨性关节炎关节液和血浆的研究 蛋白质组学，这可能会为关节特异性和系统性对骨关节炎的贡献提供新的见解 病理生理学需要确定新的生物标记物，并建议新的治疗策略。