Magnetic Capture of Osteoarthritis Biomarkers

 描述(由申请人提供)：骨关节炎(OA)是一种痛苦的、衰弱的疾病，与重大的社会经济负担有关。许多治疗骨性关节炎的潜在疗法如果能够在疾病的早期阶段应用，可能会更有效，为了促进这一点，发展早期骨性关节炎的诊断学是未来骨性关节炎治疗的迫切需要。不幸的是，评估小关节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地开发新的OA诊断和预后生物标志物的能力。我们团队开发了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记物，而不需要抽吸关节液。利用磁捕获，我们已经证明了比目前的方法更准确和更灵敏地从大鼠膝盖检测OA生物标记物的能力。这项建议的目的是促进磁捕获作为一种方法来评估动物安乐死后的啮齿动物骨关节炎模型中的多个生物标志物(目标1)，并作为一种方法来评估活体动物的生物标志物水平(目标2)。这些进展将有助于通过啮齿动物骨关节炎模型开发预后生物标记物，改进对新兴骨关节炎疗法的临床前评估，并展示将磁捕获应用于人类小关节(如手部关节)骨关节炎生物标记物分析的长期潜力。这个应用侧重于两个多目标的特定目标。在目标1中，磁捕获将被推进作为啮齿动物联合水平的骨关节炎生物标记物评估的死后分析方法，通过完成下列目标：(1.1)开发多重方法在单个磁捕获程序中检测多个骨关节炎生物标记物，(1.2)改进磁探针设计以提高磁纳米颗粒捕获的效率，(1.3)在小鼠骨关节炎模型中证明磁捕获的可行性和实用性，以及(1.4)评估关节水平的骨关节炎生物标记物、关节退变的组织学证据和骨关节炎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，磁捕获将被推进作为啮齿动物联合水平的骨关节炎生物标志物评估的体内分析方法：(2.1)设计用于体内捕获骨关节炎生物标记物的颗粒和靶向分子，(2.2)设计基于导管的注射/收集装置用于体内捕获磁性纳米颗粒，(2.3)评估用于体内磁捕获的磁性颗粒的清除性、安全性和生物相容性，以及(2.4)使用体内磁捕获纵向评估大鼠的联合水平的骨关节炎生物标记物。这些目的和目标的成功完成将有助于更好地了解骨关节炎相关的发病机制和骨关节炎相关的疼痛和残疾之间的联系，从而有能力开发诊断和预后的骨关节炎生物标志物，从而改善骨关节炎患者的预后。朝着这一目标迈出的重要一步是开发一种能够在小关节关节滑液中进行纵向OA生物标记物评估的技术。在这项提案中，我们将推进我们的新型磁捕获技术来满足这一需求。

 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.