A Novel Contrast Agent for Post-Traumatic Osteoarthritis Imaging

项目摘要 创伤后骨关节炎（PTOA）是一种常见的严重并发症，可发生在急性膝关节炎 前交叉韧带（ACL）断裂。手术重建无法阻止 PTOA的发展，表明损伤后关节的急性生化变化触发了PTOA的发生。 导致PTOA的一连串事件。对损伤的炎症反应的持续被假设为 在关节退行性变的过程中的重要因素，因此代表了一个有吸引力的治疗目标。在 一般来说，在PTOA中观察到的炎症是慢性的、低度的，主要由先天性免疫系统介导。 系统虽然已经确定了几种机制可以激活炎症反应， 在体外，我们对体内炎症反应如何发生知之甚少，因为我们缺乏技术， 追踪体内的炎症目前评估PTOA炎症的方法要么是破坏性的， 组织学上，不像炎症因子的分析那样具有组织特异性，或者缺乏生物学特异性， as imaging成像.分子成像是解决PTOA发病机制的自然方法，因为它 可以在分子水平上对炎症过程进行成像，并完全覆盖关节。我们的研究旨在 开发一种新的造影剂，通过使用一种肽， 特异性靶向细胞表面受体，其在炎症信号传导和组织修复中发挥重要作用。 我们建议使用一种多模态成像方法，结合磁共振成像（MRI）和近场成像。 红外（NIR）成像。我们将进行实验以在体外验证造影剂并评估其 体内早期和晚期的药代动力学。最后，我们将在纵向研究中测试造影剂。 该建议的结果将提供一个平台，以阐明PTOA的病理生理学，帮助识别 新的治疗靶点和跟踪治疗反应。本申请中开发的分子探针具有 由于其靶点跨物种保留，因此具有人类临床转化的潜力。

Project Summary Posttraumatic osteoarthritis (PTOA) is a common and serious complication that can occur following acute knee injury, such as anterior cruciate ligament (ACL) rupture. The inability of surgical reconstruction to prevent the development of PTOA, suggests that acute biochemical changes in the joint following injury trigger the cascade of events leading to PTOA. Perpetuation of the inflammatory response to injury is hypothesized as an important factor in the process of joint degeneration, thus representing an attractive target for therapy. In general, the inflammation observed in PTOA is chronic, low-grade, mediated primarily by the innate immune system. Although several mechanisms have been identified that can activate the inflammatory response in vitro, there is little known on how the inflammatory response occurs in vivo, since we lack the technology to track inflammation in vivo. Current methods to assess inflammation in PTOA are either destructive like histology, are not tissue-specific like the analysis of inflammatory factors, or lack the biological specificity such as imaging. Molecular imaging represents a natural approach to address the pathogenesis of PTOA, since it can image inflammation processes at the molecular level with complete joint coverage. Our research aims to develop a new contrast agent to image low-grade inflammation in PTOA in vivo by using a peptide that specifically target cell surface receptors, which play important roles in inflammatory signaling and tissue repair. We propose to use a multimodal imaging approach combining magnetic resonance imaging (MRI) and near infrared (NIR) imaging. We will conduct experiments to validate the contrast agent in vitro and to assess its pharmacokinetics at early and late stage in vivo. Lastly, we will test the contrast agent in a longitudinal study. The results of this proposal will provide a platform to elucidate the pathophysiology of PTOA, help identifying new therapeutic targets, and track therapy response. The molecular probe developed in this application has potential for human clinical translation since its targets are preserved cross-species.