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.

项目总结/摘要 我是一名风湿病学家和博士培训的流行病学家，我的职业生涯致力于以患者为导向的研究 (POR)重点是骨关节炎（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 我很好地追求高质量的POR，但也为我提供了必要的技能，以培养下一代 临床科学家。在过去的十年里，我表现出了对导师制的坚定承诺， 辅导或共同辅导POR的21名受训人员。这些辅导活动成功地为 大多数学员，包括一个可资助的K23分数的初级教师。此外，所有继续执行 临床研究，除一人外，其余均进行流变学相关研究，4名现任住院医师 学员有兴趣从事流变学的临床研究事业。这个K24奖项将使我能够 扩大和扩展这些成功的指导努力，使我可以作为一个更大的主要导师 通过确保我有时间保护和救济从未来的临床和行政职责的学员人数。 这个K24补助金的主要目标是：1）支持我作为主要导师的持续发展和影响 在POR中，新重点是初级教师，特别是K申请者和获奖者，以及那些从 K to R奖; 2）在波士顿为POR建立一个新的正式的流变学研究导师培训计划 大学医学院（BUSM）;以及3）在一个新的方向上提高我自己的POR，以便我继续 进行科学严谨和有意义的POR。由于我对POR的承诺和迄今为止的指导， BUSM和临床流行病学单位拥有丰富的资源，以及强大的机构支持，K24 提供了一个宝贵的机会，以扩大我的指导能力的初级教师作为主要的导师， 特别强调女性临床研究人员，并建立一个专门的结构化POR和导师 流变学培训课程，对学员和导师进行正式评估。 除了指导，我的长期目标之一是继续提高我公认的研究能力。 这项研究利用了我在OA和痛风方面的专业知识，并与专家合作， 有互补专业知识的人来加强我的研究计划。强大的支持 基于生物学原理，我建议研究尿酸盐（痛风的病理生理学罪魁祸首） 和办公自动化。我将研究膝关节内局部尿酸盐沉积与 在一项由NIH资助的大型队列研究中，3000名受试者使用了一种新的成像技术，即双能量CT， 能够区分尿酸盐与其他形式的晶体沉积（如钙），以及MRI上的OA病理 和痛苦我还将对滑液进行最先进的蛋白质组学分析， 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，如 滑膜炎拟议的研究所要解决的知识差距将提供新的见解， 骨关节炎是一种目前尚无治疗方法的疾病。此外，委员会认为， 拟议的研究将提供极好的指导机会。这K24赠款将大大增加我的 在POR现有的研究指导计划，使我能够招募和作为主要导师，以2-3个新的 学员和初级教师每年，与发展下一代的病人为导向的最终目标 风湿病临床研究者和研究导师。