Project 3: Intraarticular Mineralization

项目3：关节内矿化

• 批准号: 10555688
• 负责人: TUHINA NEOGI
• 金额: $ 75.52万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555688
• 关键词: Acute; Address; Algorithms; Anatomy; Anti-Cytokine Therapy; Arthritis; Blood; C-reactive protein; Calcium; Calcium Pyrophosphate; Calcium pyrophosphate deposition disease; Cartilage; Collection; Crystal Formation; Data; Degenerative polyarthritis; Development; Disease; Foundations; IL18 gene; Image; Image Analysis; Incidence; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Joints; Knee; Knee Osteoarthritis; Knowledge; Location; Magnetic Resonance Imaging; Meniscus structure of joint; Methods; Modification; Outcome; Pain; Pathology; Pathway interactions; Pattern; Persons; Phenotype; Physics; Placebos; Prevalence; Prevention strategy; Proteomics; Pseudogout; Questionnaires; Replacement Arthroplasty; Research; Role; Serum; Shoulder; Spectroscopy, Fourier Transform Infrared; Subgroup; Symptoms; Synovial Fluid; Testing; Traction; Urate; Work; X-Ray Computed Tomography; calcification; calcium phosphate; cardiovascular risk factor; clinically relevant; cytokine; deep learning; differential expression; experience; inflammatory marker; innovation; insight; knee pain; mineralization; novel; radiological imaging; soft tissue; systemic inflammatory response; treatment strategy; two-dimensional; ultrasound

ABSTRACT Project 3: Intra-Articular Mineralization Intra-articular (IA) mineralization due to calcium crystal deposition is common in knee osteoarthritis (OA), and may contribute to inflammation, structural pathology, and pain. However, prior studies have been conflicting regarding its clinical relevance, likely partly due to reliance on relatively insensitive radiographs. In addition, the particular crystal type may have different consequences in OA. We plan to address these key knowledge gaps by use of dual energy CT (DECT) to more sensitively detect IA mineralization, and apply a novel image analysis method to differentiate type of crystal present in the IA mineralization. We hypothesize that IA calcium crystal deposition may induce low-grade inflammation that can contribute to pain and its fluctuation in OA. Further, particular types of calcium crystal (calcium pyrophosphate [CPP] vs. basic calcium phosphate [BCP]) may contribute differently to OA outcomes. Clarification of potential consequences of IA mineralization and specific crystal types in knee OA would enable examination of IA mineralization as a treatment target in OA with therapies such as anti-IL-1β or other anti-cytokine therapy addressing inflammation due to crystals. We will leverage data collected in the Multicenter Osteoarthritis (MOST) Study, including previously acquired DECT and stored blood biospecimens, and take advantage of the planned synovial fluid acquisition in conjunction with the proposed MOST4 Project 4 on synovial fluid proteomics. Using these rich data, we propose to evaluate the following: 1) the relation of IA mineralization to pain fluctuation over two years; 2) the relation of IA mineralization to serum inflammatory markers; 3) type of crystal (CPP vs. BCP) and volume of each type using novel DECT image analysis, and determine the extent to which each crystal type is related to serum inflammatory signatures, structural progression, and pain; 4) To examine the synovial inflammatory signatures via proteomics in knees with crystal-proven CPP vs. BCP (exploratory pilot aim). We will work with Dr. Fabio Becce who has developed the novel image analysis methods to differentiate crystal type on DECT, as well as with Dr. Ann Rosenthal who will use Fourier transform infrared spectroscopy to identify crystal type in synovial fluid to permit proteomics analysis of synovial fluid containing CPP vs. BCP. In exploratory analysis using deep learning, we will evaluate the relationship of crystal type to co-localized predicted cartilage loss. These proposed studies are innovative as they will provide novel insights into the inter-relationships between IA crystals, inflammation, pain, and pathology in OA. The proposed research is significant as such insights would lay the foundation for identifying an important OA phenotype targetable by effective anti-cytokine therapy leading to disease modification. This would provide an important breakthrough for this disease in which there are no disease-modifying therapies available to date.

摘要项目3：关节内矿化 由于钙晶体沉积引起的关节内（IA）矿化在膝骨关节炎（OA）中很常见， 可能导致炎症、结构病理学和疼痛。然而，先前的研究一直相互矛盾， 关于其临床相关性，可能部分是由于依赖于相对不敏感的X光片。此外该 特定的晶体类型在OA中可能具有不同的结果。我们计划解决这些关键的知识差距 通过使用双能CT（DECT）更灵敏地检测IA矿化，并应用新型图像分析 方法来区分IA矿化中存在的晶体类型。我们假设IA钙晶体 沉积可诱导低度炎症，其可导致OA中的疼痛及其波动。此外，本发明还 特定类型的钙晶体（焦磷酸钙[CPP]对碱性磷酸钙[BCP]）可 对OA结果的贡献不同。阐明IA矿化的潜在后果和具体 膝关节OA中的晶体类型将能够检查IA矿化作为OA治疗靶点， 例如抗IL-1β或其它抗细胞因子治疗，解决由于晶体引起的炎症。我们将利用数据 在多中心骨关节炎（MOST）研究中采集，包括既往获得的DECT和储存的血液 生物标本，并利用计划的滑液采集与建议的 MOST 4项目4滑液蛋白质组学。利用这些丰富的数据，我们建议评估以下内容：1） IA矿化与两年以上疼痛波动的关系：2）IA矿化与血清 炎症标志物; 3）晶体类型（CPP与BCP）和使用新型DECT图像的每种类型的体积 分析，并确定每种晶体类型与血清炎症特征相关的程度， 结构进展和疼痛; 4）通过蛋白质组学检查膝关节滑膜炎症特征 与晶体证明CPP与BCP（探索性试点目标）。我们将与法比奥·贝奇博士合作， 新的图像分析方法，以区分晶体类型的DECT，以及与博士安罗森塔尔谁 将使用傅里叶变换红外光谱法来识别滑液中的晶体类型，以允许蛋白质组学 含有CPP与BCP的滑液的分析。在使用深度学习的探索性分析中，我们将评估 晶体类型与共定位预测软骨损失的关系。这些建议的研究是创新的， 他们将为IA晶体、炎症、疼痛和病理学之间的相互关系提供新的见解 在OA。拟议的研究是重要的，因为这些见解将奠定基础，确定一个重要的 OA表型可通过有效的抗细胞因子治疗靶向，导致疾病改善。这将提供 这是对这种疾病的一个重要突破，迄今为止还没有可用的疾病修饰疗法。