Genomic and Imaging Markers to Understand and Predict Progression of Joint Damage After Injury

项目总结 摘要创伤后骨关节炎是前十字韧带损伤后的主要并发症。 (前交叉韧带)破裂。在美国，每年有超过100,000例前交叉韧带断裂，其中70%发生在身体上 40岁以下的活跃受试者。据估计，在前交叉韧带断裂后10到20年，PTOA的患病率 50-70%，无论手术或非手术治疗。预防PTOA导联的手术失败 对于损伤后关节的剧烈变化会引发一系列事件的假设 导致了PTOA。然而，关于生物对损伤的反应如何与随后的关节联系起来，我们知之甚少。 损坏。因此，重要的是要有可提供全面响应评估的工具 目的：预测前交叉韧带损伤后谁会发生PTOA。即使候选生物标记物已经 经过调查，它们的实际使用仍然非常有限。这项提议的目标是调查生物反应 滑液中可溶性生物标志物测定及细胞外基因组图谱分析对损伤的影响 在18-40岁的前交叉韧带损伤的急性期和亚急性期，从SF分离出小泡(EVS)。 年龄较大的患者有可能在损伤后3-4年和6-7年预测关节退化。差异 患者之间对前交叉韧带损伤的生物学反应涉及不同细胞类型的存在和 不同的细胞反应。电动汽车，这是由所有类型的电池释放，是有吸引力的候选人作为All-in-in- 其一，复杂的生物标志物能够提供多方面的、集成的、快照的整个 联合环境。此外，鉴于这些脂类双层分隔的颗粒携带大量蛋白质，不同 来自其亲代细胞的RNA和脂质的类型，以及EVS可以调节靶细胞，使这些 颗粒作为生物标志物更具吸引力。为了测量关节损伤的进展，我们将使用高级 我们实验室开发的核磁共振生物标记物可以检测早期组织退变，特别是关节软骨退变， 组织，这是PTOA早期诊断的关键。更重要的是，我们的核磁共振标记显示 预测进程的能力。我们的目标是验证我们的假设，即对货物捕获的伤害的早期反应 将提供一个新的窗口，直接了解关节损伤后的早期生物学变化 导致PTOA的关节损伤的进展。为了实现我们的目标建立一个生物标志物档案来预测 对于损伤的生物学反应以及最终PTOA的发展，我们提出了两个目标。目标1将 在受伤后(受伤后2至3周)和手术时(8至12周)直接提供一组生物标志物 损伤后)建立对损伤的生物反应，并确定这些生物标志物与 基线核磁共振测量关节损伤。在目标2中，我们将测试这些生物标志物是否可以预测变化 于伤后3~4年和6~7年判定临床和影像结果。最后，我们将建立一个 关节退化预测生物标记物小组经临床采用的经济有效的方法验证 布景。

PROJECT SUMMARY Posttraumatic osteoarthritis (PTOA) is a major complication that follows an episode anterior cruciate ligament (ACL) rupture. In the US, there are over 100,000 ACL ruptures per year, from which 70% occur in physically active subjects under 40 years of age. At 10 to 20 years after ACL rupture the prevalence of PTOA is estimated to be 50–70%, regardless of surgical or non-surgical interventions. The failure of surgery to prevent PTOA leads to the hypothesis that the acute changes in the joint following directly after injury triggers a cascade of events leading to PTOA. However, little is known about how biological response to injury links to the subsequent joint damage. Therefore, it is important to have tools available that provide comprehensive assessment of response to injury and predict who will develop PTOA after ACL injury. Even though candidate biomarkers have been investigated, their practical use is still very limited. The goal of this proposal is to investigate if biological response to injury by measuring soluble biomarkers in synovial fluid (SF) and analyzing the genomic profile of extracellular vesicles (EVs) isolated from SF obtained during the acute and sub-acute phases of ACL injuries of 18- to 40- years old patients has the potential to predict joint degradation at 3-4 and 6-7 years after injury. Differences between patients in the biological responses to ACL injury involve the presence of different cell types and different cellular responses. EVs, which are being released by all cell types, are attractive candidates as all-in- one, complex biomarkers able to provide a multi-faceted, integrated, snapshot “omics” joint profile of the entire joint environment. In addition, given that these lipid bilayer–delimited particles carry cargos of proteins, different types of RNA, and lipids derived from their parent cells, and that EVs can modulate target cells, make these particles even more attractive as biomarkers. To measure progression of joint damage we will use advanced MRI biomarkers developed in our labs that can detect early tissue degeneration, especially of articular cartilage, a tissue, which is key in the early diagnosis of PTOA. Even more importantly, our MRI markers have shown ability to predict progression. We aim to test our hypothesis that early response to injury captured by the cargo of EVs will provide a new window into early biological changes directly after joint injury is associated with progression of joint damage leading to PTOA. To achieve our goal to establish a biomarker profile that predicts the biological response to the injury and ultimately the development of PTOA, we propose two aims. Aim 1 will provide a panel of biomarkers directly after injury (2 to 3 weeks after injury) and at time of surgery (8 to 12 weeks after injury) establishing the biological response to injury, and determine the relation of these biomarkers to baseline MRI measures of joint damage. In Aim 2, we will test whether these biomarkers can predict changes in the clinical and imaging outcomes determined 3-4 years and 6-7 years after injury. Finally, we will establish a panel of predictive biomarkers for joint degradation validated by cost-effective methods employed in the clinical setting.