PEARL: Pathway Exploration and Analysis in Renal Lupus

 描述（由申请方提供）：肾炎是系统性红斑狼疮的一种常见且严重的表现，目前尚无适当的治疗方法。一些患者将表现出对当前免疫抑制方案的反应，而另一些则不会;所有患者都有靶向和脱靶毒性的风险。目前的建议是应用新技术对狼疮活动性肾炎患者的肾脏、血液和尿液进行基因表达和免疫表型的高分辨率分析，以便更好地了解疾病发病机制和组织损伤，并对患者的治疗反应进行分层，以便做出更明智的临床决策。我们将探索血液和尿液中用于肾脏炎症的侵入性较小的替代标记物。我们的计划依赖于优化分析方法，明智地选择要分析的细胞亚群，然后进行两项小型研究来完善和验证该方法。首先，我们将研究20名患者在肾爆发时的肾脏、血液和尿液，以剖析炎症的模式。第二，我们 将研究40名狼疮性肾炎临床试验患者血液中的细胞亚群，以了解对治疗有完全临床反应和无反应的患者的基因表达和功能反应基线概况的变化。最后，我们将利用这些研究的信息设计一个大规模的狼疮性肾炎患者的纵向研究。对这一未满足的医学挑战进行公正的重新审视，应该能够识别新的治疗靶点，为新的疾病模型的产生提供信息，并产生可以在临床试验中验证的反应预测因子。我们拥有独特的技术资源和强大的临床研究人员联盟新成立的狼疮性肾炎试验网络包括：（i）临床研究实施的基础设施和专业知识;（ii）用于采集血液、尿液和活检样本的协议和同意;以及（3）在适当的时间从阶段0和1移动到阶段2的可缩放性。

 DESCRIPTION (provided by applicant): Nephritis is a common and serious manifestation of Systemic Lupus Erythematosus for which there is no adequate therapy. Some patients will exhibit a response to current immunosuppressive regimens while others will not; all are at risk for on and off target toxicities. The current proposal is to apply new technologies for high resolution analyses of gene expression and immunophenotype to kidney, blood and urine of lupus patients with active nephritis in order to develop a better understanding of disease pathogenesis and tissue injury, and stratify patients with respect to therapeutic response for more informed clinical decision making. We will explore blood and urine for less invasive surrogate markers for kidney inflammation. Our plan relies of optimization of analytic approaches, informed choice of cellular subpopulations to analyze, followed by two small studies to refine and validate the approach. In the first, we will study kidneys, blood and urine o 20 patients at a time of renal flare in order to dissect patterns of inflammation. In the second we will study cellular subsets in blood of 40 patients who were part of a clinical trial of lupus nephritis to understand changes from baseline profiles of gene expression and function response in those who experienced a full clinical response to therapy and those who failed to respond. Finally, we will use the information from these studies to design a large scale longitudinal study of patients with lupus nephritis. This unbiased re-examination of this unmet medical challenge should identify novel therapeutic targets, inform the generation of new models of disease, and lead to predictors of response that can then be validated in clinical trials We have unique technology resources and a powerful consortium of clinical investigators in the newly established Lupus Nephritis Trials Network that includes: (i) the infrastructure and expertise for clinical study implementation; (ii) protocols and consents for acquisition of blood, urine, and biopsy specimens; and (3) scalability to move from phase 0 and 1 to phase 2 at the appropriate time.