Genetically-engineered stem cells for self-regulating arthritis therapy

项目摘要/摘要 类风湿关节炎(RA)是最常见的慢性炎症性和破坏性关节疾病，影响1% 占世界人口总数的一半。滑膜组织内炎症过程的永久化导致局部 组织降解酶的激活和骨吸收破骨细胞的形成，引发进行性 软骨和骨骼破坏。因此，早期诊断炎症过程，预防骨质疏松症 软骨的破坏是维系类风湿关节炎功能的关键。目前，类风湿性关节炎的早期评估 活动和对治疗的反应主要包括体检、患者报告和实验室。 分析。因此，显然有必要为RA患者开发基于精确的治疗方法，同时 非侵入性分子成像预测治疗反应，限制不良事件和无效 治疗。常规X线片仍是评估结构骨和软骨的首选方法。 类风湿关节炎患者的损害。新的成像方法，如正电子发射断层扫描/计算机联合成像 体层摄影术(PET/CT)提供对病理生理过程的洞察以及全身解剖 本地化。18F-FDG已被用于定位RA患者的关节炎症过程； 不仅显示炎症关节对18F-FDG的摄取增加，而且与疾病有很强的相关性 活动。使用骨示踪剂18F-NaF的PET成像显示，RA、骨关节炎和 骨质疏松。我们的团队已经开发出基于细胞的植入物，可以提供多种抗细胞因子疗法 以自我调节方式治疗类风湿性关节炎(RA)或其他自身免疫性疾病 持续时间。我们的方法是纵向描述关节炎症和骨骼的类型和强度。 侵蚀以确定反映对所用治疗的敏感性或抵抗力的变化。整体而言 翻译的目标是利用具有成像生物标志物的成像方法来评估NEXT的疗效 使用类风湿性关节炎的活体小鼠模型进行基于细胞的治疗。这种方法将使我们能够系统地 验证我们的中心假设：RA炎症和骨质侵蚀将在治疗干预后逆转。至 以特定部位的方式检验这一假设，我们将评估滑膜和滑膜的时空代谢变化 骨利用18F-FDG和18F-NaF PET/CT。我们使用分子成像的综合方法 生物标志物将更好地为我们对小鼠不同生物疗法的评估提供信息。我们预计这项研究将 提供数据，改变我们目前对类风湿关节炎治疗和干预反应的理解。这项研究 将影响旨在确定个性化治疗的未来研究和临床试验的设计 风湿性和其他肌肉骨骼炎症情况。在吉拉克和范博士的指导下， 这份增刊将让我实现我的职业发展目标，成为一名独立翻译 科学家致力于通过开发成像生物标记物来促进患者的健康 诊断、监测和预测炎症性关节炎基于细胞的治疗结果。

PROJECT SUMMARY/ABSTRACT Rheumatoid arthritis (RA) is the most common chronic inflammatory and destructive joint disease, affecting 1% of the population worldwide. Perpetuation of inflammatory processes within the synovial tissue leads to local activation of tissue‐degrading enzymes and formation of bone‐resorbing osteoclasts, provoking progressive cartilage and bone destruction. Therefore, early diagnosis of inflammatory processes and prevention of bone and cartilage destruction are crucial to preserve function in RA. Currently, early assessment of RA disease activity and response to therapy mainly consists of physical examination, patient reports, and laboratory analyses. Thus, there is a clear need to develop precision-based therapy for patients with RA in tandem with non-invasive molecular imaging to predict therapeutic response, and limit adverse events and ineffective therapies. Conventional radiography remains the first choice for the assessment of structural bone and cartilage damage in RA patients. Novel imaging methods, such as combined positron emission tomography/computed tomography (PET/CT) provide insights into pathophysiological processes together with whole-body anatomical localization. 18F-FDG has been used to localize articular inflammatory processes in patients suffering from RA; showing not only increased uptake of 18F-FDG in inflamed joints, but also a strong correlation with disease activity. PET imaging with the bone tracer 18F-NaF has shown high bone turnover in RA, osteoarthritis, and osteoporosis. Our group has developed cell-based implants that can deliver multiplexed anti-cytokine therapies for treating rheumatoid arthritis (RA) or other autoimmune diseases in a self-regulating manner for extended durations. Our approach is to longitudinally characterize pattern and intensity of joint inflammation and bone erosion to identify changes that reflect sensitivity or resistance to the therapy administered. The overall translational goal is to leverage imaging methodologies with imaging biomarkers to assess the efficacy of next generation cell-based therapies using in vivo mouse models of RA. This approach will enable us to systematically test our central hypothesis: RA inflammation and bone erosion will be reversed after therapeutic intervention. To test this hypothesis in a site-specific manner, we will assess spatio-temporal metabolic changes in synovium and bone leveraging 18F-FDG and 18F-NaF PET/CT. Our comprehensive approach using molecular imaging biomarkers will better inform our assessment of different biologic therapies in mice. We expect this study to provide data that shifts our current understanding about RA therapies and intervention response. This research will influence the design of future studies and clinical trials aimed at identifying personalized therapies in rheumatic and other musculoskeletal inflammatory conditions. Under the mentorship of Drs. Guilak and Pham, this supplement will allow me to achieve my career development goal of becoming an independent translational scientist with research focused on promoting the health of patients by developing imaging biomarkers to diagnose, monitor, and predict outcomes of cell-based therapies in inflammatory arthritis.