Protein Phenotyping of SLE Nephritis Flare Cycle

描述(由申请人提供)：人类系统性红斑狼疮的肾脏受累很常见，通常很严重。治疗通常是有效的，但伴随着相当大的毒性。如果治疗能够及早开始，根据疾病的严重程度量身定做，并在注定会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，需要预测SLE肾功能衰竭发作、病情严重程度和治疗反应的生物标志物。这个试点项目的目标是确定是否可以通过检测整个肾扩张周期的尿蛋白组来模拟SLE肾扩张的表型。这项工作将利用俄亥俄州立大学开发的俄亥俄州系统性红斑狼疮研究数据库和标本库，其中包含一系列临床信息以及来自一组SLE患者的尿样和血浆样本，这些样本在5年内每2个月前瞻性地跟踪一次。目的1利用表面增强激光解吸电离飞行时间质谱仪(SELDI-TOF-MS)检测系统性红斑狼疮(SLE)患者肾炎发作前、发作期间及治疗后尿蛋白质组变化的可行性。肾脏红斑发生前表达变化的蛋白质可能是即将发生红斑和/或红斑严重程度的预报者。FLARE期间差异表达的蛋白质可能与肾脏损伤的发病机制有关，因此可能反映潜在的新的治疗靶点。FLARE治疗后蛋白质的变化可能有助于预测治疗反应。Aim 2将测试在Aim 1中使用液相色谱-串联质谱仪(LLC-Tandem MS)对SELDI-TOF-MS检测到的差异表达蛋白质进行阳性鉴定的可行性。在Aim 3中，AIM 2中确定的候选SLE肾炎生物标记物将使用基于免疫检测或定量质谱学的技术在原始样本集中进行定量。综上所述，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记物识别和验证的可行性。公共卫生相关性：这项研究将促进开发新的诊断工具来预测系统性红斑狼疮肾功能衰竭的发病、严重程度和结果。这些工具将基于系统性红斑狼疮肾脏疾病发作期间尿蛋白的变化。这将导致更早的诊断和治疗，从而更有效地利用目前可用的药物，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.