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

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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.