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提案，旨在帮助主要研究者实现和扩大其 K08 奖项的目标，同时有助于收集足够的初步数据以申请联邦 NIH R01 资助。首席研究员目前拥有指导职业发展奖 K08 AR064834-01，题为“胆碱激酶：类风湿性关节炎的新靶点”，并由 Drs.法尔斯坦、卡琳和卡瓦诺。她职业发展的要点之一是培养在风湿病领域以患者为导向的研究中进行独立调查所需的技能，更准确地说是获得利用代谢组学研究进行生物标志物分析的经验。她的 K08 旨在通过磁共振波谱法探索胆碱代谢物及其下游产物作为类风湿性关节炎关节损伤的诊断或预后生物标志物的作用。初步数据表明，通过质谱将这一目标扩展为更详细的研究，并对成纤维细胞样滑膜细胞（FLS）和类风湿性关节炎（RA）患者血清中的代谢物进行非靶向研究，将有助于实现这一目标。代谢组学是生物标志物研究的一个新兴领域。基于可以利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。用于诊断或预测类风湿性关节炎 (RA) 不同治疗反应的生物标志物仍然是一个未满足的医疗需求，特别是对于对 TNF 阻滞剂没有反应的患者或进行性关节损伤的患者。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，导致其攻击行为和关节破坏。有趣的是，胆碱代谢是肿瘤学中潜在的预后标志物。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，并作为一个具体目标，我们将通过磁共振波谱法 (MRS) 和超高效液相色谱质谱法 (UPLC-MS) 更精确地分析静息 FLS 中以及 RA 相关细胞因子刺激后的胆碱代谢物和下游效应物。将分析细胞和上清液中的代谢物，以确定最合适的代谢物作为生物标志物。非针对性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人和其他炎症性疾病患者相比，FLS 中检测到的代谢物在 RA 患者的血清或尿液样本中也可检测到。将确定由 DAS28 确定的所选代谢物、血清阳性、糜烂性疾病和疾病活动之间的关系。如果成功，我们的研究可以转化为重要的诊断和预后测试，识别 FLS 激活和关节损伤高风险的患者，并确定最合适的治疗方法。