Protein Phenotyping of SLE Nephritis Flare Cycle

SLE 肾炎发作周期的蛋白质表型

• 批准号: 7679470
• 负责人: BRAD H ROVIN
• 金额: $ 18.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679470
• 关键词: Aftercare; Biological; Biological Markers; Clinical; Complication; Data; Databases; Development; Disease; Early Diagnosis; Evolution; Flare; Goals; Growth Factor; Hormones; Human; Inflammatory; Injury; Investigation; Kidney; Kidney Diseases; Lead; Liquid Chromatography; Liquid substance; Mass Spectrum Analysis; Measurement; Measures; Mediator of activation protein; Methods; Modeling; Molecular Weight; Monitor; Morbidity - disease rate; Nephritis; Ohio; Onset of illness; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Plasma; Positioning Attribute; Proteins; Proteome; Proteomics; Research; Sampling; Screening procedure; Sensitivity and Specificity; Severities; Severity of illness; Specimen; Systemic Lupus Erythematosus; Techniques; Testing; Therapeutic Uses; Therapeutic immunosuppression; Time; Toxic effect; Universities; Urine; Validation; Work; base; capillary liquid chromatography; clinical assay development; cohort; cytokine; design; disorder control; effective therapy; improved; insight; new therapeutic target; novel diagnostics; outcome forecast; protein expression; protein profiling; public health relevance; response; surface enhanced laser desorption ionization; tandem mass spectrometry; tool

DESCRIPTION (provided by applicant): Kidney involvement in human SLE is common and usually severe. Treatment is often effective, but accompanied by considerable toxicity. Morbidity from treatment could be considerably reduced if it could be started early, tailored to disease severity, and tapered off quickly in patients destined to have a durable response. To use therapy in this way requires biomarkers that predict the onset of SLE renal flare, the severity of the flare, and the response to therapy. The goal of this pilot project is to determine whether the phenotype of SLE renal flare can be modeled by examining the urine proteome throughout the renal flare cycle. This work will utilize the Ohio SLE Study database and specimen bank, developed at the Ohio State University, and which contains serial clinical information and urine and plasma samples from a cohort of SLE patients followed prospectively every 2 months over 5 years. Aim 1 will use surface-enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS) to test the feasibility of profiling changes in the urine proteome of SLE patients before renal flare onset, during flare, and following treatment of flare. Proteins that change expression before a renal flare may be forecasters of impending flare and/or flare severity. Proteins that are differentially expressed during flare may be relevant to the pathogenesis of kidney injury, and may thus reflect potential novel therapeutic targets. Proteins that change after flare treatment may be useful in predicting response to treatment. Aim 2 will test the feasibility of using liquid chromatography-tandem mass spectrometry to positively identify differentially expressed proteins detected by SELDI-TOF-MS in Aim 1. In Aim 3, candidate SLE nephritis biomarkers identified in Aim 2 will be quantified in the original sample set using immunodetection or quantitative mass spectrometery-based techniques. In summary, this project is expected to demonstrate the feasibility of biomarker identification and validation by monitoring changes in the urine proteome during the SLE nephritis flare cycle. PUBLIC HEALTH RELEVANCE: This research will facilitate the development of novel diagnostic tools to predict onset, severity, and outcome of SLE renal flare. These tools will be based on changes in urine proteins during SLE renal flares. This will lead to earlier diagnosis and treatment, and thus more effective use of currently available medications, resulting in improved clinical outcomes for SLE nephritis.

描述（由申请人提供）：人类 SLE 中肾脏受累很常见，而且通常很严重。治疗通常是有效的，但伴随着相当大的毒性。如果治疗能够尽早开始，根据疾病的严重程度进行调整，并在注定有持久反应的患者中迅速逐渐减少，那么治疗的发病率可能会大大降低。要以这种方式使用治疗，需要生物标志物来预测 SLE 肾脏发作、发作的严重程度以及对治疗的反应。该试点项目的目标是确定是否可以通过检查整个肾发作周期的尿液蛋白质组来模拟 SLE 肾发作的表型。这项工作将利用俄亥俄州立大学开发的俄亥俄州 SLE 研究数据库和样本库，其中包含来自 SLE 患者队列的系列临床信息以及尿液和血浆样本，这些患者在 5 年内每 2 个月进行一次前瞻性随访。目标 1 将使用表面增强激光解吸/电离飞行时间质谱 (SELDI-TOF-MS) 来测试分析 SLE 患者肾脏发作前、发作期间和发作治疗后尿液蛋白质组变化的可行性。在肾脏发作前改变表达的蛋白质可能是即将发生的发作和/或发作严重程度的预测因子。在发作期间差异表达的蛋白质可能与肾损伤的发病机制有关，因此可能反映潜在的新治疗靶点。急性发作治疗后发生变化的蛋白质可能有助于预测治疗反应。目标 2 将测试使用液相色谱-串联质谱法来积极鉴定目标 1 中由 SELDI-TOF-MS 检测到的差异表达蛋白的可行性。在目标 3 中，将使用免疫检测或基于定量质谱的技术对原始样本集中在目标 2 中识别的候选 SLE 肾炎生物标志物进行定量。总之，该项目有望通过监测 SLE 肾炎发作周期期间尿液蛋白质组的变化来证明生物标志物识别和验证的可行性。公众健康相关性：这项研究将促进新型诊断工具的开发，以预测 SLE 肾发作的发病、严重程度和结果。这些工具将基于 SLE 肾脏发作期间尿蛋白的变化。这将导致更早的诊断和治疗，从而更有效地使用现有药物，从而改善系统性红斑狼疮肾炎的临床结果。