Choline metabolites as biomarkers in rheumatoid arthritis

胆碱代谢物作为类风湿性关节炎的生物标志物

• 批准号: 8895115
• 负责人: Monica Guma
• 金额: $ 7.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895115
• 关键词: Address; Aggressive behavior; Arthritis; Award; Betaine; Biological; Biological Markers; Biomedical Research; Blood; Cartilage; Cell Line; Cell Proliferation; Cells; Choline; Choline Kinase; Chronic; Clinical; Data; Diagnosis; Diagnostic; Disease; Fibroblasts; Goals; Grant; Health; Hour; Immune; Inflammation Mediators; Inflammatory; Invaded; Investigation; K-Series Research Career Programs; Laboratories; Lecithin; Lupus; Lysophosphatidylcholines; Lysophospholipids; MS4A1 gene; Magnetic Resonance; Malignant Neoplasms; Mass Spectrum Analysis; Mediator of activation protein; Medical; Mentors; Metabolism; Outcome; Pathogenesis; Patients; Performance; Phenotype; Phosphatidylserines; Phosphocreatine; Phospholipids; Phosphorylcholine; Physiological; Platelet-Derived Growth Factor; Play; Principal Investigator; Prognostic Marker; Recruitment Activity; Research; Research Proposals; Rest; Rheumatoid Arthritis; Rheumatology; Role; Sampling; Serum; Spectrometry; Sphingomyelins; Sphingosine; Staging; Stress; Synovitis; TNF gene; Techniques; Testing; Time; Translating; United States National Institutes of Health; Urine; Variant; arthropathies; articular cartilage; base; bone; cancer cell; career development; ceramide 1-phosphate; clinical phenotype; cytokine; experience; functional disability; high risk; improved; interest; joint destruction; joint injury; liquid chromatography mass spectrometry; metabolomics; novel; oncology; patient oriented research; platelet-derived growth factor BB; prognostic; repository; response; skills; sphinganine; sphingosine 1-phosphate; sphingosine phosphorylcholine; therapeutic target; treatment strategy; tumor progression

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.

描述（由申请人提供）：该提案描述了一项为期三年的研究建议，旨在帮助首席研究人员实现和扩大其K08奖的目标，同时，它将有助于收集足够的初步数据以申请联邦NIH R01赠款。主要研究人员目前颁发了指导的职业发展奖K08 AR064834-01，标题为“胆碱激酶：类风湿关节炎的新型目标”，并由DRS指导。 Firestein，Karin和Kavanaugh。她职业发展的要点之一是开发在风湿病领域以患者为导向研究的独立研究所需的技能集，更精确地使用代谢组学研究获得了生物标志物分析的经验。她的K08旨在探索胆碱代谢产物及其下游产品的作用，作为通过磁共振光谱法在类风湿关节炎中关节损伤的诊断或预后生物标志物。初步数据表明，将这一目标扩展到质谱法的更详细的研究中，并意识到对成纤维细胞样的滑膜细胞（FLS）和类风湿关节炎患者血清中代谢产物的无靶向研究将有助于实现这一目标。代谢组学是生物标志物研究中的新新兴领域。基于可以使用代谢组的生理信息追踪疾病的假设，代谢物水平的变化可用于生物标志物研究。生物标志物可用于诊断或预测类风湿关节炎（RA）的不同治疗方法的反应（RA）仍然是未满足的医疗需求，尤其是在对TNF阻滞剂或进行性关节损害的患者中无反应的患者中。我们最近将胆碱激酶确定为RA中潜在的治疗靶点。胆碱代谢在FLS功能中起着重要作用，这有助于其攻击性行为和关节破坏。有趣的是，胆碱代谢是肿瘤学的潜在预后标志。我们的长期目标是确定胆碱代谢产物或其他代谢产物作为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，作为一个特定目标，我们将分析静止FLS中更精确的胆碱代谢产物和下游效应子，以及用磁共振光谱法（MRS）和超强液体色谱量质谱法（UPLC-MS）涉及RA的细胞因子刺激后。将在细胞和上清液中分析代谢物，以确定最合适的代谢物作为生物标志物。非目标分析还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患者和其他炎症性疾病的患者相比，在FL中检测到的I代谢物可在RA患者的血清或尿液样本中检测到。由DAS28确定的选择的代谢产物，血清阳性，侵蚀性疾病和疾病活动之间的关系。如果成功的话，我们的研究可能会转化为重要的诊断和预后测试，这些测试将确定患有FLS激活和关节损害风险的患者，并确定最合适的疗法。