PEARL: Pathway Exploration and Analysis in Renal Lupus

 描述(申请人提供)：肾炎是系统性红斑狼疮的一种常见而严重的表现，目前尚无适当的治疗方法。一些患者会对目前的免疫抑制方案表现出反应，而另一些患者则不会；所有患者都面临着时而时而发生靶标毒性的风险。目前的建议是应用新技术对狼疮活动性肾炎患者的肾脏、血液和尿液进行高分辨率的基因表达和免疫表型分析，以更好地了解疾病的发病机制和组织损伤，并根据治疗反应对患者进行分层，以便做出更明智的临床决策。我们将探索血液和尿液中侵入性较小的肾脏炎症替代标志物。我们的计划依赖于分析方法的优化，明智地选择要分析的细胞亚群，然后进行两个小规模的研究来完善和验证方法。首先，我们将研究20例肾功能衰竭患者的肾脏、血液和尿液，以便解剖炎症模式。在第二天，我们 将研究40名参与狼疮性肾炎临床试验的患者血液中的细胞亚群，以了解那些经历了治疗完全临床有效和无效的患者的基因表达和功能反应基线图谱的变化。最后，我们将利用这些研究的信息来设计一项针对狼疮性肾炎患者的大规模纵向研究。对这一尚未满足的医学挑战的公正重新检查应该确定新的治疗目标，为新疾病模型的产生提供信息，并产生可在临床试验中验证的反应预测因素。在新建立的狼疮性肾炎试验网络中，我们拥有独特的技术资源和强大的临床研究人员联盟，其中包括：(I)临床研究实施的基础设施和专业知识；(Ii)采集血液、尿液和活组织标本的协议和同意；以及(3)在适当的时候从0和1阶段转移到2阶段的可伸缩性。

 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.