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

基因组和成像标记物可了解和预测受伤后关节损伤的进展

• 批准号: 10605787
• 负责人: THORSTEN KIRSCH
• 金额: $ 74.58万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605787
• 关键词: Acute; Address; Age Years; Biological; Biological Markers; Biological Testing; Cartilage; Cells; Clinical; Clinical Research; Clinical assessments; Complex; Complication; Development; Diffusion Magnetic Resonance Imaging; Disease; Early Diagnosis; Environment; Event; Failure; Fatty acid glycerol esters; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Genomics; Goals; Homeostasis; Image; Inflammation; Injury; Intervention; Joints; Link; Lipid Bilayers; Lipids; Magnetic Resonance Imaging; Measures; Meniscus structure of joint; Methods; Molecular; Operative Surgical Procedures; Orthopedic Surgery; Outcome; Parents; Pathology; Patients; Phase; Play; Population; Positioning Attribute; Prevalence; Proteins; RNA; Research; Risk Factors; Role; Sampling; Severities; Symptoms; Synovial Fluid; Testing; Time; Tissue-Specific Gene Expression; Tissues; Traumatic Arthropathy; Untranslated RNA; Validation; anterior cruciate ligament injury; anterior cruciate ligament rupture; articular cartilage; biobank; biomarker panel; candidate marker; cell type; clinical application; cohort; cost effective; diagnostic tool; disability; extracellular vesicles; follow-up; genomic biomarker; genomic profiles; healing; imaging biomarker; imaging modality; joint destruction; joint injury; magnetic resonance imaging biomarker; novel diagnostics; older patient; outcome prediction; participant enrollment; particle; posttranscriptional; predictive marker; predictive panel; predictive tools; prevent; prospective; recruit; response; response to injury; tissue degeneration; tool

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.

项目摘要 创伤后骨关节炎（PTOA）是前交叉韧带损伤后的一种主要并发症 (ACL)破裂在美国，每年有超过100，000例ACL断裂，其中70%发生在身体上。 40岁以下的活跃受试者。在ACL断裂后10至20年，估计PTOA的患病率 50- 70%，无论手术或非手术干预。手术预防PTOA电极导线失败 假设损伤后关节的急性变化直接引发了一系列事件， 导致PTOA。然而，很少有人知道如何生物反应损伤链接到随后的关节 损害因此，重要的是要有工具，对应对措施进行全面评估 预测ACL损伤后PTOA的发生率。尽管候选生物标志物已经被 经过调查，它们的实际用途仍然非常有限。这项提案的目的是调查生物反应是否 通过测量滑液（SF）中的可溶性生物标志物和分析细胞外 从18- 40岁ACL损伤的急性和亚急性期获得的SF中分离的囊泡（EV）， 岁的患者有可能预测损伤后3-4年和6-7年的关节退化。差异 患者之间对ACL损伤的生物学反应涉及不同细胞类型的存在， 不同的细胞反应。电动汽车，这是正在释放的所有细胞类型，是有吸引力的候选人，因为所有在- 一个复杂的生物标志物，能够提供一个多方面的，综合的，快照“组学”联合概况的整个 联合环境。此外，考虑到这些脂质双层界定的颗粒携带蛋白质货物，不同的脂质分子可能会产生不同的蛋白质。 RNA类型和来自其亲本细胞的脂质，以及EV可以调节靶细胞，使这些 作为生物标记物更有吸引力。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MRI生物标志物可以检测早期组织退化，特别是关节软骨， 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 预测进展的能力。我们的目标是验证我们的假设，即货物对伤害的早期反应 的EV将提供一个新的窗口，以了解关节损伤后的早期生物学变化， 导致PTOA的关节损伤进展。为了实现我们的目标，建立一个生物标志物谱，预测 对损伤的生物学反应和最终PTOA的发展，我们提出两个目标。目标1将 在损伤后（损伤后2至3周）和手术时（8至12周）提供一组生物标志物 损伤后）建立对损伤的生物学反应，并确定这些生物标志物与 关节损伤的基线MRI测量。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 在伤后3-4年和6-7年确定的临床和影像学结果中。最后，我们将建立一个 通过临床中采用的具有成本效益的方法验证的关节退化预测生物标志物组 设置.