Project 2: Synovial Fluid Proteomics

项目2：滑液蛋白质组学（原项目4） 骨关节炎（OA）是关节炎的最常见形式，也是老年人身体残疾的主要原因。 个体除了缓解症状外，没有批准的药物治疗， 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： 血液和关节内生物标志物之间的差异以及生物力学的主要影响， 使得难以区分OA的系统性和机械性贡献。可能存在差异 单部位膝关节与手部和膝关节发生的多部位OA之间的差异，因为后者可能由以下原因引起 系统启动而不是关节特异性因素。关节特异性滑液中蛋白质的评估 与关节组织和配对血浆直接接触可以提供对关节特异性和全身性 OA的因素。拟定的研究将填补膝关节和多部位OA病理生物学知识的空白。 本提案的目的是使用蛋白质组学方法， 配对滑液和血浆的分析。我们的核心假设是， 在滑液和血浆中，可用于鉴定OA的生物标志物， 从关节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，并提供对疾病发病机制的见解。我们将评估返回 来自多中心骨关节炎研究（MOST）的参与者， 年龄在54-86岁之间的个体，以评估膝关节OA发病率和进展的风险因素。所有参与者 将在MOST 4访视1时接受手部和膝关节OA的影像学评估。将收集滑液 在膝关节超声检查显示至少有1 ml滑液的患者中（约500名受试者），其中包括 那些有和没有频繁的膝盖疼痛。我们将测量约500对滑液和血液中的蛋白质 使用SOMAScan（一种基于适体的蛋白质组学检测方法，可同时检测约7，000种 proteins. MOST中的蛋白质组学发现将在一个国际财团STEpUP OA中得到复制， 包括来自5个队列的约1，800名个体，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OA滑液和血浆中与膝关节疼痛相关的蛋白质， 软骨损伤目的2将鉴定膝关节OA滑液和血浆中与膝关节OA纵向病变相关的蛋白质。 膝关节疼痛恶化或MRI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 与多部位OA相关。这一建议的预期成果是鉴定蛋白质组签名 OA发病机制的基础。这将是第一个和最大的研究配对OA滑液和血浆 蛋白质组学，这可能会提供新的见解关节特异性和系统性的贡献，OA 病理生理学需要鉴定新的生物标志物，并提出新的治疗策略。

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.