Protein Phenotyping of SLE Nephritis Flare Cycle

描述（由申请人提供）：人类SLE的肾脏受累很常见，通常很严重。治疗通常是有效的，但伴随着相当大的毒性。如果能够及早开始治疗，根据疾病的严重程度量身定制，并在患者中迅速逐渐减少，从而产生持久的反应，那么治疗的死亡率可以大大降低。以这种方式使用治疗需要生物标志物来预测SLE肾发作、发作的严重程度和对治疗的反应。本试验项目的目的是确定是否可以通过检查整个肾耀斑周期的尿蛋白质组来模拟SLE肾耀斑的表型。这项工作将利用俄亥俄州SLE研究数据库和标本库，该数据库和标本库是在俄亥俄州州立大学开发的，其中包含来自SLE患者队列的系列临床信息和尿液和血浆样本，这些患者在5年内每2个月前瞻性随访一次。目的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患者在肾耀斑发作前、耀斑期间和治疗后尿蛋白质组变化的可行性。在肾爆发前改变表达的蛋白质可能是即将发生的爆发和/或爆发严重程度的预测者。发作期间差异表达的蛋白质可能与肾损伤的发病机制相关，因此可能反映潜在的新治疗靶点。耀斑治疗后发生变化的蛋白质可能有助于预测对治疗的反应。目的2将测试使用液相色谱-串联质谱法来阳性鉴定目的1中通过SELDI-TOF-MS检测到的差异表达蛋白的可行性。在目标3中，目标2中鉴定的候选SLE肾炎生物标志物将使用免疫检测或基于定量质谱的技术在原始样品集中进行定量。总之，该项目有望通过监测SLE肾炎发作周期中尿蛋白质组的变化来证明生物标志物鉴定和验证的可行性。公共卫生相关性：这项研究将有助于开发新的诊断工具，以预测SLE肾发作的发作，严重程度和结果。这些工具将基于SLE肾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的药物，从而改善SLE肾炎的临床结果。

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.