This proposal describes a five year mentored research program in laboratory and clinical based research essential to the development of the principal investigator as an independent investigator. The principal investigator has completed her medical studies, specializing in Rheumatology, and Ph.D. studies in Immunology in Barcelona, Spain. She then moved to San Diego to join Dr. Michael Karin's lab for her postdoctoral training in signal transduction. She is now realizing Rheumatology Fellowship at the University of California at San Diego and will expand upon her research skills through a focused individualized career development plan. The program will provide training in molecular and cell biology of synovial fibroblasts and arthritis models applied to chronic inflammation and rheumatoid arthritis (RA). By the end of her award period, she will also have developed the skill sets required to conduct independent investigation in pre-clinical translational research, and patient-oriented research in the field of Rheumatology. Her studies will also require additional training in proteomics, NMR, and metabolomics that will provide her with important new tools that can be applied to her research as an independent investigator. Dr. Gary S. Firestein is a professor of medicine and dean of translational research institute at UC San Diego and will mentor the principal investigator's scientific development. Dr. Firestein is a recognized leader in signal transduction and pathogenesis of rheumatoid arthritis and has a strong record of mentoring physician scientists. Dr. Michael Karin is also a recognized leader in signal transduction and inflammation will provide additional guidance as a co-mentor in this filed. Dr. Kavanaugh, as a clinical mentor, will assist with developing novel biomarkers using patient samples. Of note, the principal investigator has no experience in biomarker analysis synovial fibroblast biology, patient-oriented research, and clinical trials and those skills would be essential for transition to an independent investigator. In addition, our collaborators will help wth the use of the technology and informatics for metabolomics studies, with the interpretation of results and how it can be applied to developing new biomarkers. Didactic courses, seminars, journal clubs and 80% protected time for specific training in laboratory techniques in a supportive academic environment in the Department of Medicine at UCSD will complement the training program. The research proposal will focus on the role of choline kinase in chronic inflammation and joint destruction associated with RA. In addition, these studies will determine whether this enzyme is a potential therapeutic target to treat inflammatory disorders. We will also explore the role of this kinase and its downstream products as diagnostic or prognostic biomarker. The proposal builds upon preliminary studies demonstrating a novel function of choline kinase in proliferation and survival of fibroblast-like synoviocytes derived from RA patients. The proposed studies will explore function and regulation of choline kinase in key signaling events, inflammation and joint destruction in RA. In addition, expression, function and regulation of choline kinase will be determined in cells and tissue samples derived from patients with RA. The relationship between the choline kinase metabolites pattern and disease activity as determined by clinical disease measures will be determined
The proposed studies have direct significance for understanding mechanism of rheumatoid arthritis and may lead to novel therapeutic approaches. Rheumatoid arthritis is a chronic, debilitating condition and affects about 1% of the population in United States. There is a need for more effective, safer and affordable therapies.
| Falconer, Jane; Murphy, Anne N; Young, Stephen P et al. (2018) Review: Synovial Cell Metabolism and Chronic Inflammation in Rheumatoid Arthritis. Arthritis Rheumatol 70:984-999 |
| Friedman, Beth; Whitney, Michael A; Savariar, Elamprakash N et al. (2018) Detection of Subclinical Arthritis in Mice by a Thrombin Receptor-Derived Imaging Agent. Arthritis Rheumatol 70:69-79 |
| Stubelius, Alexandra; Sheng, Wangzhong; Lee, Sangeun et al. (2018) Disease-Triggered Drug Release Effectively Prevents Acute Inflammatory Flare-Ups, Achieving Reduced Dosing. Small 14:e1800703 |
| Narasimhan, Rekha; Coras, Roxana; Rosenthal, Sara B et al. (2018) Serum metabolomic profiling predicts synovial gene expression in rheumatoid arthritis. Arthritis Res Ther 20:164 |
| Garcia-Carbonell, Ricard; Wong, Jerry; Kim, Ju Youn et al. (2018) Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death. Proc Natl Acad Sci U S A 115:E9192-E9200 |
| Bustamante, Marta F; Oliveira, Patricia G; Garcia-Carbonell, Ricard et al. (2018) Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis. Ann Rheum Dis 77:1636-1643 |
| Coras, Roxana; Narasimhan, Rekha; Guma, Monica (2018) Liquid biopsies to guide therapeutic decisions in rheumatoid arthritis. Transl Res 201:1-12 |
| Viger, Mathieu L; Collet, Guillaume; Lux, Jacques et al. (2017) Distinct ON/OFF fluorescence signals from dual-responsive activatable nanoprobes allows detection of inflammation with improved contrast. Biomaterials 133:119-131 |
| Bustamante, Marta F; Garcia-Carbonell, Ricard; Whisenant, Katrijn D et al. (2017) Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res Ther 19:110 |
| Guma, Monica; Tiziani, Stefano; Firestein, Gary S (2016) Metabolomics in rheumatic diseases: desperately seeking biomarkers. Nat Rev Rheumatol 12:269-81 |
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