PEARL: Pathway Exploration and Analysis in Renal Lupus

PEARL：肾狼疮的通路探索与分析

• 批准号: 10186964
• 负责人: Betty Diamond
• 金额: $ 59.92万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186964
• 关键词: Adverse effects; Bioinformatics; Biological; Biopsy Specimen; Blood; Blood specimen; Cells; Cessation of life; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Consent; Data; Disease; Disease model; End stage renal failure; Enrollment; Ensure; Event; Exhibits; Expression Profiling; Flare; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genetic Transcription; Goals; Hematopoietic; Histologic; Immune; Immunophenotyping; Immunosuppression; Individual; Infertility; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Infrastructure; Intervention; Kidney; Lead; Longitudinal Studies; Lupus; Lupus Nephritis; Malignant Neoplasms; Measures; Medical; Methods; Molecular; Molecular Profiling; Nephritis; Opportunistic Infections; Osteoporosis; Outcome; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Phase; Phenotype; Pilot Projects; Prediction of Response to Therapy; Protocols documentation; RNA; Regimen; Renal Tissue; Research Design; Research Personnel; Resolution; Resources; Risk; Sampling; Site; Surrogate Markers; Systemic Lupus Erythematosus; Techniques; Technology; Therapeutic; Time; Tissues; Toxic effect; Tumor-infiltrating immune cells; Urine; clinical decision-making; conventional therapy; design; experience; gene function; improved; insight; interest; interstitial; kidney biopsy; nephritis therapy; new technology; new therapeutic target; novel; pathogen; patient stratification; phase 1 study; phase 2 study; predicting response; public health relevance; response; rheumatologist; single-cell RNA sequencing; therapeutic target; tissue injury; tissue repair; transcriptome sequencing; treatment response

 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.

 描述（由申请人提供）：肾炎是系统性红斑狼疮的常见且严重的表现，目前尚无适当的治疗方法。一些患者会对当前的免疫抑制疗法产生反应，而另一些患者则不会；所有人都面临着靶标和脱靶毒性的风险。目前的建议是应用新技术对活动性肾炎狼疮患者的肾脏、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，寻找肾脏炎症的侵入性较小的替代标记物。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 名患者在肾脏发作时的肾脏、血液和尿液，以剖析炎症的模式。在第二个我们 将研究参与狼疮肾炎临床试验的 40 名患者血液中的细胞亚群，以了解对治疗产生全面临床反应和未能反应的患者的基因表达和功能反应基线谱的变化。最后，我们将利用这些研究的信息设计一项针对狼疮性肾炎患者的大规模纵向研究。对这一未满足的医学挑战进行公正的重新审查应该确定新的治疗靶点，为新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。我们在新建立的狼疮肾炎试验网络中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）用于临床研究实施的基础设施和专业知识； (ii) 采集血液、尿液和活检标本的协议和同意书； (3) 可扩展性，可在适当的时间从阶段 0 和阶段 1 转移到阶段 2。