The Role of Inflammation in Knee Osteoarthritis

项目摘要： 症状性膝关节骨关节炎（OA）影响着美国1400万成年人，是一个主要原因 残疾人。越来越多的人认识到OA中不同的表型， 针对特定表型的疗法。关节内炎症表现为滑膜炎， 作为与疼痛和结构进展相关的重要表型特征出现。 这项建议的重点是了解滑膜炎的作用及其地形和颞叶 对疼痛的影响及其作为治疗靶点的潜力。第一个目标是调查是否 一个人的膝关节之间渗出液滑膜炎的不一致性预示着不同的疼痛 在膝盖之间报告。我们将纵向研究滑膜炎的变化 超过24个月与疼痛的变化有关。这些分析将包括调整 膝关节和个体水平的疼痛贡献者，以更好地确定 滑膜炎疼痛。第二个目标是使用超声波，这是一种容易获得且廉价的成像方法 技术，以检查是否存在渗出性滑膜炎在膝关节确定一个 在关节内类固醇注射后疼痛将有更大的减少。最后， 目标3将利用对轻度、中度和重度滑膜炎患者的滑膜进行单细胞RNA测序 以更好地定义在各种OA阶段活跃的细胞类型和转录谱。如果， 正如我们所怀疑的那样，炎症在疾病过程的早期更占主导地位， 炎性疗法可能在早期OA中最有效。 这个资助机会和项目是专门针对我的过渡到一个 独立调查员和R01资金。我将有保护的时间为这个项目和 独特的支持和丰富的学术环境，可以接触到世界领先的导师， 课程，和职业发展系列通过哈佛医学院，哈佛T.H. 陈公共卫生学院和布莱根妇女医院。具体而言，这一目标 建议将提供先进的分层，集群和纵向经验 统计建模，在分析中使用超声和磁共振成像变量， 和滑膜的RNA测序。这些目标和教育机会将给我 深入了解研究OA炎症关键方面的方法， 使我能够领导未来关于新OA疗法的时机和靶点的工作。

Project Summary: Symptomatic knee osteoarthritis (OA) affects 14 million adults in the U.S. and is a leading cause of disability. There is growing recognition of distinct phenotypes within OA and the need to tailor therapies to specific phenotypes. Intra-articular inflammation manifesting as synovitis has emerged as an important phenotypic feature associated with pain and structural progression. This proposal centers on understanding the role of synovitis and its topographic and temporal effects on pain as well as its potential as a treatment target. The first aim investigates whether discordance in effusion-synovitis between an individual’s knees portends differential pain reporting between the knees. Longitudinally we will investigate whether changes in synovitis over 24 months are associated with changes in pain. These analyses will include adjustment for both knee and individual level contributors to pain to better ascertain the independent effect of synovitis on pain. The second aim uses ultrasound, a readily available and inexpensive imaging technique, to examine whether the presence of effusion-synovitis in the knee identifies a subgroup that will have a greater reduction in pain after intra-articular steroid injection. Lastly, aim 3 will utilize single-cell RNA sequencing of the synovium in patients with mild, moderate and severe OA to better define cell types and transcriptional profiles active at various OA stages. If, as we suspect, inflammation is more predominant early in the disease process, anti- inflammatory therapies may be most effective in early OA. This funding opportunity and project are specifically geared toward my transitioning to an independent investigator and R01 funding. I will have protected time for this project and a uniquely supportive and rich academic environment with access to world-leading mentors, coursework, and career development series through the Harvard Medical School, Harvard T.H. Chan School of Public Health and Brigham and Women’s Hospital. Specifically, the aims in this proposal will provide experience with advanced hierarchical, clustered and longitudinal statistical modeling, use of ultrasound and magnetic resonance imaging variables in analysis, and RNA sequencing of the synovium. These aims and educational opportunities will give me an in-depth understanding of methods to investigate key facets of inflammation in OA, positioning me to lead future work on the timing and targeting of novel OA therapies.