The Role of Inflammation in Knee Osteoarthritis

炎症在膝骨关节炎中的作用

• 批准号: 10599268
• 负责人: Lindsey A. MacFarlane
• 金额: $ 15.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599268
• 关键词: Accounting; Address; Adrenal Cortex Hormones; Adult; Affect; Anti-Inflammatory Agents; Attenuated; Bilateral; Biological Markers; Biometry; Cells; Characteristics; Clinical; Complex; Data; Degenerative polyarthritis; Development; Disease; Education; Environment; Epidemiology; Exhibits; Funding; Funding Opportunities; Future; Gene Expression Profile; Goals; Hospitals; Image; Imaging Techniques; Immunology; Individual; Inflammation; Inflammatory; Injections; Knee; Knee Osteoarthritis; Lead; Magnetic Resonance Imaging; Mentors; Methods; Modeling; Molecular; Orthopedics; Pain; Pain Measurement; Pain management; Patient Recruitments; Patients; Phenotype; Positioning Attribute; Process; Public Health Schools; Radiology Specialty; Registries; Reporting; Research; Research Personnel; Rheumatology; Role; Sensory; Series; Severities; Statistical Models; Steroids; Subgroup; Synovial Cell; Synovial Membrane; Synovitis; Testing; Time; Tissues; Woman; Work; career development; cell type; cohort; design; disability; disease natural history; effective therapy; effusion; experience; individualized medicine; knee pain; medical schools; multidisciplinary; novel; osteoarthritis pain; pain relief; prognostic model; radiological imaging; recruit; repaired; response; single-cell RNA sequencing; transcriptome sequencing; transcriptomics; ultrasound

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.

项目概要： 有症状的膝骨关节炎 (OA) 影响着美国 1,400 万成年人，并且是主要原因 的残疾。人们越来越认识到 OA 中的不同表型以及定制的必要性 针对特定表型的疗法。关节内炎症表现为滑膜炎 成为与疼痛和结构进展相关的重要表型特征。 该提案的重点是了解滑膜炎的作用及其地形和时间 对疼痛的影响及其作为治疗目标的潜力。第一个目标是调查是否 个体膝盖之间积液滑膜炎的不一致预示着不同的疼痛 报告在膝盖之间。我们将纵向研究滑膜炎是否发生变化 超过 24 个月与疼痛变化相关。这些分析将包括调整 膝盖和个人层面的疼痛因素，以更好地确定疼痛的独立影响 滑膜炎就疼痛。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技术 技术，检查膝关节积液滑膜炎是否存在识别 关节内类固醇注射后疼痛会得到更大程度减轻的亚组。最后， 目标 3 将利用单细胞 RNA 测序对患有轻度、中度和 严重的 OA 可以更好地定义在不同 OA 阶段活跃的细胞类型和转录谱。如果， 正如我们怀疑的那样，炎症在疾病过程的早期更为占主导地位， 炎症治疗可能对早期 OA 最有效。 这个资助机会和项目专门针对我过渡到 独立研究者和 R01 资助。我将为这个项目提供受保护的时间 独特的支持性和丰富的学术环境，可以接触到世界领先的导师， 哈佛医学院、哈佛 T.H. 课程作业和职业发展系列 陈公共卫生学院和布莱根妇女医院。具体来说，本次活动的目标 提案将提供先进的分层、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， 让我领导未来关于新型 OA 疗法的时机和目标的工作。