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

项目摘要/摘要 我是一名风湿学家和受过博士培训的流行病学家，我的职业生涯致力于以患者为中心的研究 (POR)专注于骨关节炎(OA)和痛风，这是两种最常见的风湿病， 会导致疼痛、功能受限和生活质量下降。我的训练不仅让我 很好地追求高质量的POR，也为我提供了培养下一代所需的技能 临床科学家。在过去的十年里，我表现出了对导师制的坚定承诺 指导或共同指导21名POR受训人员。这些辅导活动成功地为 这些学员中的大多数，包括一名初级教职员工，他们的K23分数是可以资助的。此外，所有人都继续表现 临床研究，除1人外均从事与风湿病相关的研究，4名现任住院医师 学员对从事风湿病临床研究事业感兴趣。这个K24奖将使我能够 扩大和延伸这些成功的指导努力，这样我就可以作为一个更大的 通过确保我有保护的时间和未来的临床和行政职责的缓解来减少受训者的数量。 这笔K24助学金的主要目标是：1)支持我作为主要导师的持续发展和影响 在POR中，新的重点是初级教师，特别是K申请者和获奖者，以及那些从 K to R奖；2)在波士顿为风湿病POR建立一个新的正式研究导师培训计划 大学医学院(BUSM)；以及3)在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。到目前为止，我对POR和指导的承诺， BUSM和临床流行病学单位提供的丰富资源，以及强有力的机构支持，K24 提供了一个宝贵的机会来扩大我作为主要导师的初级教员的指导能力， 特别重视女性临床研究人员，并建立专门的结构化POR和导师 风湿病培训课程，并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。 建议的研究利用了我在OA和痛风方面的成熟专业知识，以及与 这些领域的人有互补的熟练程度，以加强我的研究计划。得到强大的支持 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。 以及使用新技术的办公自动化。我将检查膝关节内局部尿酸盐沉积的关系。 在一项由美国国立卫生研究院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，该技术 使尿酸盐与其他形式的晶体沉积(如钙)和MRI上的OA病理区分开来 也敬痛苦。我还将对滑液进行最先进的蛋白质组学分析，以辨别尿酸盐的影响 膝关节骨性关节炎滑液中的炎性介质及其与骨性关节炎炎症特征的关系 滑膜炎。拟议的研究将解决知识差距问题，这将为 潜在的新的治疗目标是骨性关节炎，这是一种目前尚无治疗方法的疾病。此外， 拟议的研究将提供极好的指导机会。这笔K24拨款将大大增加我的 POR中现有的研究指导计划，使我能够招聘并担任2-3名新的 每年培训实习生和初级教员，最终目标是培养以患者为导向的下一代 风湿病临床研究人员和研究导师。

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.