Magnetic Capture of Osteoarthritis Biomarkers

 描述（由申请人提供）：骨关节炎（OA）是一种疼痛、使人衰弱的疾病，与显著的社会经济负担相关。如果能够在疾病早期阶段应用，许多潜在的OA治疗方法可能会更有效，为了促进这一点，开发早期OA的诊断方法是未来OA治疗的关键需求。不幸的是，评估小关节的关节水平变化的技术还不发达，这些技术限制阻碍了我们有效开发新的OA诊断和预后生物标志物的能力。我们的团队已经开发出一种新的基于磁性纳米颗粒的技术，可以直接从小关节提取生物标志物，而无需抽吸滑液。使用磁捕获，我们已经证明了从大鼠膝关节中检测OA生物标志物的能力，其准确性和灵敏度高于目前的方法。本提案的目的是推进磁捕获作为评估动物安乐死后啮齿动物OA模型中多种生物标志物的方法（目的1），以及评估活体动物中生物标志物水平的方法（目的2）。这些进展将有助于通过啮齿动物OA模型开发预后生物标志物，改善新兴OA治疗的临床前评估，并证明将磁捕获应用于小型人类关节（如人手）中OA生物标志物分析的长期潜力。该应用程序侧重于两个多目标的具体目标。在目标1中，通过完成以下目标，将磁捕获作为啮齿动物关节水平OA生物标志物评估的死后分析方法：（1.1）开发多重方法以在单一磁性捕获程序中检测多种OA生物标志物，（1.2）改进磁性探针设计以增加磁性纳米颗粒捕获的效率，（1.3）证明磁捕获在小鼠OA模型中的可行性和实用性，以及（1.4）评价关节水平OA生物标志物、关节退行性变的组织学证据和OA症状的行为证据之间的联系。在目标2中，通过完成以下目标，将磁捕获作为啮齿动物关节水平OA生物标志物评估的体内分析方法：（2.1）设计用于体内捕获OA生物标志物的颗粒和靶向分子，（2.2）设计用于磁性纳米颗粒的体内捕获的基于导管的注射/收集装置，（2.3）评估用于体内磁捕获的磁性颗粒的清除率、安全性和生物相容性，以及（2.4）使用体内磁捕获在大鼠中纵向评估关节水平OA生物标志物。成功完成这些目的和目标将有助于更好地了解OA相关发病机制与OA相关疼痛和残疾之间的联系，从而能够开发诊断和预后OA生物标志物，改善OA患者的结局。实现这一目标的一个重要步骤是开发一种能够在小关节滑液中进行纵向OA生物标志物评估的技术。在这项提案中，我们的新型磁捕获技术将被推进，以满足这一需求。

 DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a painful, debilitating disease associated with a significant socioeconomic burden. Many potential therapeutics for OA would likely be more effective if they could be applied at early disease stages, and to facilitate this, development of diagnostics for early stage OA is a critical need for the future of OA therapy. Unfortunately, technologies to assess joint-level changes in small articular joints are underdeveloped, and these technological limits impede our ability to effectively develop new diagnostic and prognostic biomarkers for OA. Our group has developed a new magnetic nanoparticle based technology to extract biomarkers directly from small articular joints without the need to aspirate synovial fluid. Using magnetic capture, we have demonstrated the ability to detect an OA biomarker from a rat knee with greater accuracy and sensitivity than current methods. The objective of this proposal is to advance magnetic capture as a method to assess multiple biomarkers in rodent OA models following animal euthanasia (Aim 1) and as a method to assess biomarker levels in live animals (Aim 2). These advances will help enable the development of prognostic biomarkers through rodent OA models, improve the preclinical assessment of emerging OA therapeutics, and demonstrate the long-term potential to apply magnetic capture to OA biomarker analysis in small human joints, such as those of the human hand. This application focuses on two, multi-objective specific aims. In Aim 1, magnetic capture will be advanced as post mortem analysis method of joint-level OA biomarker assessment in rodents by completing the following objectives: (1.1) Develop multiplex methods to detect multiple OA biomarkers in a single magnetic capture procedure, (1.2) Refine the magnetic probe design to increase the efficiency of the magnetic nanoparticle capture, (1.3) Demonstrate feasibility and utility of magnetic capture in a mouse OA model, and (1.4) Evaluate links between joint-level OA biomarkers, histological evidence of joint degeneration, and behavioral evidence of OA symptoms. In Aim 2, magnetic capture will be advanced as an in vivo analysis method of joint-level OA biomarker assessment in rodents by completing the following objectives: (2.1) Design particles and targeting molecules for the in vivo capture of OA biomarkers, (2.2) Design a catheter-based injection/collection apparatus for the in vivo capture of magnetic nanoparticles, (2.3) Assess the clearance, safety, and biocompatibility of magnetic particles used for in vivo magnetic capture, and (2.4) Longitudinally assess a joint-level OA biomarker in the rat using in vivo magnetic capture. Successful completion of these Aims and Objectives will lead to better understand the links between OA-related pathogenesis and OA-related pain and disability, and thereby an ability to develop diagnostic and prognostic OA biomarkers that will improve patient outcomes for OA. A major step toward this goal is the development of an enabling technology for longitudinal OA biomarker assessment in the synovial fluid of small articular joints. In this proposal, our novel magnetic capture technology will be advanced to address this need.