The Role of Urate in Knee Osteoarthritis-Related Inflammation, Pathology and Pain

尿酸盐在膝骨关节炎相关炎症、病理和疼痛中的作用

• 批准号: 9223170
• 负责人: TUHINA NEOGI
• 金额: $ 15.53万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223170
• 关键词: Address; Adverse effects; Affect; American; Anatomy; Arthritis; Award; Boston; Calcium; Cartilage; Cells; Chondrocytes; Clinical; Clinical Investigator; Clinical Research; Cohort Studies; Collaborations; Crystal Formation; Crystallization; Degenerative polyarthritis; Deposition; Development; Dinoprostone; Disease; Doctor of Philosophy; Educational Curriculum; Eicosanoids; Ensure; Epidemiologist; Evaluation; Faculty; Fostering; Foundations; Functional disorder; Funding; Future; Goals; Gout; Grant; Hydroxyeicosatetraenoic Acids; Hyperuricemia; Image; Imaging technology; Immune; Individual; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Arthritis; Innate Immune System; Interleukin-1 beta; Interleukin-18; Interleukin-6; Joints; K-Series Research Career Programs; Knee; Knee Osteoarthritis; Knee joint; Knowledge; Lesion; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Medical; Mentors; Mentorship; Methodology; Mid-Career Clinical Scientist Award (K24); Outcome; PTGS2 gene; Pain; Pain management; Pathology; Pathway interactions; Persons; Play; Positioning Attribute; Proteomics; Quality of life; Recruitment Activity; Research; Research Personnel; Research Training; Resources; Rheumatism; Rheumatology; Role; Scientist; Severities; Signal Transduction; Structure; Surface; Symptoms; Synovial Fluid; Synovitis; TNF gene; Testing; Time; Training; Training Programs; Ultrasonography; United States National Institutes of Health; Universities; Urate; Woman; Work; X-Ray Computed Tomography; articular cartilage; career; clinical epidemiology; cohort; crystallinity; cytokine; disability; effective therapy; evidence base; improved; innovation; insight; interest; joint injury; knee pain; medical schools; new technology; new therapeutic target; next generation; novel; patient oriented; patient oriented research; prevent; programs; public health relevance; rheumatologist; skills; training opportunity

PROJECT SUMMARY/ABSTRACT I am a rheumatologist and PhD-trained epidemiologist who has devoted my career to patient-oriented research (POR) focused on osteoarthritis (OA) and gout, two of the most common rheumatologic conditions, which contribute to pain, functional limitations, and diminished quality of life. My training has not only positioned me well to pursue high quality POR, but has also provided me with the necessary skills to train the next generation of clinical scientists. Over the past decade, I have demonstrated a strong commitment to mentorship though mentoring or co-mentoring 21 trainees in POR. These mentoring activities have led to successful funding for the majority of those mentees, including a junior faculty with a fundable K23 score. Further, all continue to perform clinical research, with all but one conducting Rheumatology-related research, and 4 current medical resident mentees are interested in pursuing clinical research careers in Rheumatology. This K24 award would enable me to expand and extend these successful mentoring endeavors so that I may serve as primary mentor to a greater number of mentees by ensuring that I have protected time and relief from future clinical and administrative duties. The broad goals of this K24 grant are to: 1) support my continued development and impact as a primary mentor in POR with a new focus on junior faculty, particularly K applicants and awardees, and those transitioning from K to R awards; 2) establish a new formal research mentor training program for POR in Rheumatology at Boston University School of Medicine (BUSM); and 3) enhance my own POR in a novel direction so that I continue to conduct scientifically rigorous and meaningful POR. With my commitment to POR and mentoring to date, the rich resources available at BUSM and the Clinical Epidemiology Unit, and strong institutional support, the K24 provides an invaluable opportunity to expand my mentoring capacity of junior faculty as primary mentor, with a special emphasis on women clinical researchers, and to establish a specialized structured POR and mentor training curriculum in Rheumatology with formal evaluation of mentees and mentors. In addition to mentoring, one of my long-term goals is to continue advancing my recognized research capabilities. The research proposed leverages my established expertise in OA and gout, and collaboration with experts in the field who have complementary proficiencies to strengthen my research program. Supported by strong biologic rationale, I propose to study the interrelationship between urate (the pathophysiologic culprit in gout) and OA using novel technologies. I will examine the relation of local urate deposition within the knee joints of 3000 subjects in a large NIH-funded cohort study using a novel imaging technology, dual-energy CT, which enables differentiation of urate from other forms of crystal deposition such as calcium, to OA pathology on MRI and to pain. I will also conduct a state-of-the-art proteomic analysis of synovial fluid to discern the impact of urate on inflammatory mediators in knee OA synovial fluid, and the relation to inflammatory features in OA, such as synovitis. The knowledge gap to be addressed by the proposed research will provide novel insights into a potentially new therapeutic target in OA, a disease for which there are currently no therapies available. Moreover, the proposed research will provide excellent mentoring opportunities. This K24 grant would greatly augment my existing research mentoring program in POR by enabling me to recruit and act as primary mentor to 2-3 new trainees and junior faculty annually, with the ultimate goal of developing the next generation of patient-oriented rheumatic disease clinical investigators and research mentors.

项目概要/摘要 我是一名风湿病学家和受过博士学位的流行病学家，我的职业生涯致力于以患者为中心的研究 (POR) 重点关注骨关节炎 (OA) 和痛风这两种最常见的风湿病， 导致疼痛、功能限制和生活质量下降。我的训练不仅让我定位 很好地追求高质量的 POR，但也为我提供了培训下一代所需的技能 临床科学家。在过去的十年里，我表现出了对指导的坚定承诺 指导或共同指导 21 名 POR 学员。这些指导活动成功为该项目提供了资金 大多数学员，包括具有可资助 K23 分数的初级教师。此外，所有人都继续执行 临床研究，除一名外，其余所有人都在进行风湿病学相关研究，还有 4 名现任住院医生 学员有兴趣从事风湿病学的临床研究职业。这个 K24 奖项将使我 扩大和扩展这些成功的指导工作，以便我可以作为主要导师来帮助更多的人 确保我有时间并减轻未来临床和行政职责的负担，从而减少受训者的数量。 这笔 K24 资助的主要目标是：1）支持我作为主要导师的持续发展和影响力 在 POR 中，新的重点是初级教师，特别是 K 申请者和获奖者，以及从 K 至 R 奖项； 2) 在波士顿建立一个新的正式 POR 风湿病研究导师培训计划 大学医学院（BUSM）； 3）以新颖的方向增强我自己的 POR，以便我继续 进行科学严谨且有意义的 POR。凭借我对 POR 的承诺和迄今为止的指导， BUSM 和临床流行病学部门拥有丰富的资源，以及强大的机构支持，K24 提供了一个宝贵的机会来扩展我作为主要导师对初级教师的指导能力， 特别重视女性临床研究人员，并建立专门结构化的POR和导师 风湿病学培训课程，并对学员和导师进行正式评估。 除了指导之外，我的长期目标之一是继续提高我公认的研究能力。 拟议的研究利用了我在 OA 和痛风方面的既定专业知识，以及与以下领域专家的合作： 该领域具有互补的能力来加强我的研究计划。强大的支持 生物学原理，我建议研究尿酸盐（痛风的病理生理罪魁祸首）之间的相互关系 和使用新技术的 OA。我将检查膝关节内局部尿酸盐沉积的关系 NIH 资助的一项大型队列研究中有 3000 名受试者使用新型成像技术——双能 CT， 能够将尿酸盐与其他形式的晶体沉积（例如钙）区分开来，以在 MRI 上区分 OA 病理学 和痛苦。我还将对滑液进行最先进的蛋白质组学分析，以了解尿酸盐的影响 对膝关节 OA 滑液中炎症介质的影响，以及与 OA 炎症特征的关系，例如 滑膜炎。拟议研究要解决的知识差距将为以下问题提供新颖的见解： 骨关节炎（OA）的潜在新治疗靶点，目前尚无可用疗法治疗骨关节炎（OA）。而且， 拟议的研究将提供极好的指导机会。这笔 K24 补助金将大大增强我的能力 POR 中现有的研究指导计划，使我能够招募并担任 2-3 个新人的主要导师 每年培训学员和初级教师，最终目标是培养下一代以患者为中心的 风湿病临床研究者和研究导师。