This proposal describes a three-year research proposal that aims to help the principal investigator to achieve and expand the aims of her K08 award, and at the same time it will help to gather enough preliminary data to apply for federal NIH R01 grant. The principal investigator currently holds a mentored career development award, K08 AR064834-01, entitled Choline kinase: a novel target for rheumatoid arthritis and mentored by Drs. Firestein, Karin and Kavanaugh. One of the points in her career development is to develop skill sets required to conduct independent investigation in patient-oriented research in the field of Rheumatology, and more precisely to get experience in biomarker analysis using metabolomics studies. Her K08 aims to explore the role of choline metabolites and its downstream products as diagnostic or prognostic biomarker of joint damage in rheumatoid arthritis by magnetic resonance spectrometry. Preliminary data suggest that expanding this aim into a more detailed study by mass spectrometry and realizing an untargeted study of the metabolites in both fibroblast-like synoviocytes (FLS) and serum from patients with rheumatoid arthritis (RA) will help to achieve this aim. Metabolomics is a new emerging field in biomarker research. Based on the assumption that diseases can be traced using physiological information from the metabolome, the changes in metabolite levels can be used for biomarker research. Biomarkers useful in diagnosis or predicting responses to different treatments in rheumatoid arthritis (RA) remain an unmet medical need, especially in patients not responsive to TNF blockers or in patients with progressive joint damage. We have recently identified choline kinase as a potential therapeutic target in RA. Choline metabolism plays an important role in FLS functions that contribute to their aggressive behavior and joint destruction. Of interest, choline metabolism is a potential prognostic marker in oncology. Our long-term objective would be to determine suitability of choline metabolites or other metabolites as a biomarker of FLS activation and joint damage. To address this question, and as a specific goal, we will analyze more precisely choline metabolites and downstream effectors in resting FLS and after stimulation with cytokines involved in RA by magnetic resonance spectrometry (MRS) and ultra-performance liquid chromatography mass spectrometry (UPLC-MS). Metabolites will be analyzed in cells and supernatants to determine the most suitable metabolites as biomarkers. Untargeted analysis will also help to identify other potential biomarkers. We will also determine i metabolites detected in FLS are detectable in serum or urine samples of RA patients compared to normal and patients with other inflammatory diseases. The relationship between chosen metabolites, seropositivity, erosive disease, and disease activity as determined by DAS28 would be determined. If successful, our studies could translate into important diagnostic and prognostic tests that will identify patients at high risk for FLS activation and joint damage, and identify the most appropriate therapy.
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes progressive joint destruction and consequently functional disability. Biomarkers useful in diagnosis or predicting responses to different treatments in RA remain an unmet medical need, especially in patients with progressive joint damage. We propose that defining more precisely choline metabolism and its downstream metabolites in RA will identify novel biomarkers to address this need, thus if successful, could translate into important diagnostic and prognostic tests that will identify patients at high risk for joint damage and identify the most appropriate therapy.
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