Choline metabolites as biomarkers in rheumatoid arthritis

描述（由申请人提供）：本提案描述了一项为期三年的研究提案，旨在帮助主要研究者实现并扩大其K 08奖的目标，同时有助于收集足够的初步数据以申请联邦NIH R 01资助。主要研究者目前拥有一个指导职业发展奖，K 08 AR 064834 -01，题为“胆碱激酶：类风湿性关节炎的新靶点”，由Firestein，Karin和Kavanaugh博士指导。在她的职业发展的一点是发展所需的技能集进行独立的调查，以患者为导向的研究领域的流变学，更确切地说，获得经验的生物标志物分析使用代谢组学研究。她的K 08旨在通过磁共振光谱法探索胆碱代谢物及其下游产物作为类风湿关节炎关节损伤诊断或预后生物标志物的作用。初步数据表明，扩大这一目标到一个更详细的研究质谱和实现非靶向的研究成纤维细胞样滑膜细胞（FLS）和类风湿关节炎（RA）患者的血清中的代谢产物将有助于实现这一目标。代谢组学是生物标志物研究中的一个新兴领域。基于可以使用来自代谢组的生理信息来追踪疾病的假设，代谢物水平的变化可以用于生物标志物研究。用于诊断或预测类风湿性关节炎（RA）对不同治疗的反应的生物标志物仍然是未满足的医疗需求，特别是在对TNF阻断剂无反应的患者或患有进行性关节损伤的患者中。我们最近发现胆碱激酶是RA的潜在治疗靶点。胆碱代谢在FLS功能中起着重要作用，有助于其攻击行为和关节破坏。有趣的是，胆碱代谢是肿瘤学中的潜在预后标志物。我们的长期目标是确定胆碱代谢物或其他代谢物作为FLS激活和关节损伤的生物标志物的适用性。为了解决这个问题，作为一个具体的目标，我们将更精确地分析胆碱代谢物和下游效应物在静息FLS和刺激后与RA相关的细胞因子的磁共振光谱法（MRS）和超高效液相色谱质谱法（UPLC-MS）。将在细胞和上清液中分析代谢物，以确定最适合作为生物标志物的代谢物。非靶向分析也将有助于识别其他潜在的生物标志物。我们还将确定与正常和患有其他炎性疾病的患者相比，在FLS中检测到的代谢物在RA患者的血清或尿液样品中是可检测的。将确定通过DAS 28测定的所选代谢物、血清阳性、糜烂性疾病和疾病活动性之间的关系。如果成功，我们的研究可以转化为重要的诊断和预后测试，将识别FLS激活和关节损伤的高风险患者，并确定最合适的治疗方法。

DESCRIPTION (provided by applicant): 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.