The Role of Inflammation in Knee Osteoarthritis

项目总结： 症状性膝骨性关节炎(OA)在美国影响着1400万成年人，是主要原因 残疾的人。人们越来越认识到办公自动化中不同的表型，并需要量身定做 针对特定表型的治疗。表现为滑膜炎的关节内炎 出现了与疼痛和结构进展相关的重要表型特征。 这项建议的核心是理解滑膜炎的作用及其在局部和颞部的作用 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 膝关节渗出性滑膜炎的不协调性预示着不同程度的疼痛 在两膝之间报告。纵向上，我们将调查滑膜炎的变化 超过24个月与疼痛的变化有关。这些分析将包括调整 膝盖和个人水平对疼痛的贡献，以更好地确定 疼痛引起的滑膜炎。第二个目标是使用超声波，这是一种容易获得、价格低廉的成像方法 技术，以检查膝关节渗出性滑膜炎是否识别 关节内注射类固醇后疼痛有较大减轻的亚组。最后， AIM 3将利用单细胞RNA测序技术对轻、中、低年龄组患者的滑膜进行测序 严重的骨质疏松症，以更好地定义细胞类型和在不同的骨质疏松症阶段活跃的转录图谱。如果， 正如我们怀疑的那样，炎症在疾病过程的早期更占主导地位，抗- 炎性疗法可能在早期骨性关节炎中最有效。 这个融资机会和项目是专门为我过渡到 独立调查员和R01基金。我将保护这个项目的时间和一个 独特的支持性和丰富的学术环境，可以获得世界领先的导师， 课程和职业发展系列，通过哈佛医学院，哈佛T.H. 陈冯富珍公共卫生学院和布里格姆妇女医院。具体地说，这其中的目的是 建议书将提供高级分层、集群化和纵向的经验 统计建模，在分析中使用超声和磁共振成像变量， 以及滑膜的RNA测序。这些目标和教育机会将给我 深入了解研究骨性关节炎炎症关键因素的方法， 让我来领导未来在新的OA疗法的时机和目标方面的工作。

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.