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 由于钙晶体沉积导致的关节内 (IA) 矿化在膝骨关节炎 (OA) 中很常见，并且 可能会导致炎症、结构性病理学和疼痛。然而，先前的研究一直存在矛盾。 关于其临床相关性，可能部分是由于依赖相对不敏感的放射线照片。 特定的晶体类型可能会对 OA 产生不同的影响，我们计划解决这些关键的知识差距。 使用双能 CT (DECT) 更灵敏地检测 IA 矿化，并应用新颖的图像分析 区分 IA 矿化中存在的晶体类型的方法 我们追求 IA 钙晶体。 沉积可能会引起低度炎症，从而导致骨关节炎的疼痛及其波动。 特定类型的钙晶体（焦磷酸钙 [CPP] 与碱式磷酸钙 [BCP]）可能 对 OA 结果的不同贡献 澄清 IA 矿化和具体的潜在后果。 膝关节 OA 中的晶体类型可以检查 IA 矿化情况，将其作为 OA 治疗的治疗目标 例如抗 IL-1β 或其他抗细胞因子疗法来解决晶体引起的炎症。 在多中心骨关节炎 (MOST) 研究中收集，包括之前获得的 DECT 和储存的血液 生物样本，并利用计划的滑液采集与提议的结合 MOST4 滑液蛋白质组学项目 4。利用这些丰富的数据，我们建议评估以下内容：1) 2）IA矿化与血清的关系 炎症标志物；3) 使用新颖的 DECT 图像确定晶体类型（CPP 与 BCP）和每种类型的体积 分析，并确定每种晶体类型与血清炎症特征的相关程度， 结构进展和疼痛；4) 通过蛋白质组学检查膝盖滑膜炎症特征 与经晶体验证的 CPP 对比 BCP（探索性试点目标）我们将与开发的 Fabio Becce 博士合作。 在 DECT 上区分晶体类型的新颖图像分析方法，以及 Ann Rosenthal 博士 将使用傅里叶变换红外光谱来识别滑液中的晶体类型，以实现蛋白质组学 含有 CPP 与 BCP 的滑液分析 在使用深度学习的探索性分析中，我们将进行评估。 晶体类型与共定位预测软骨损失的关系这些提出的研究具有创新性。 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 拟议的研究意义重大，因为这些见解将为确定重要的基础奠定基础。 通过有效的抗细胞因子治疗可靶向 OA 表型，从而改善疾病。 这是针对这种疾病的一个重要突破，迄今为止还没有可用的疾病缓解疗法。