Multi-Ethnic Translational Research Optimization (METRO) Lupus Consortium

多民族转化研究优化 (METRO) 狼疮联盟

• 批准号: 8851808
• 负责人: Jill P Buyon
• 金额: $ 70万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851808
• 关键词: Address; Affect; Alleles; Antibodies; Archives; Asians; Biological; Biopsy; Biopsy Specimen; Blood; Blood specimen; Capillary Endothelial Cell; Cell Separation; Cells; Characteristics; Chronic; Clinical; Clinical Data; Code; Cohort Studies; Comorbidity; Complementary DNA; Copy Number Polymorphism; Cytokine Activation; Deposition; Dermal; Development; Diabetes Mellitus; Diagnostic; Disease; Drug Targeting; Early Diagnosis; Early identification; Early treatment; Endothelial Cells; Enrollment; Ethnic Origin; Evaluation; Flare; Functional RNA; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Goals; Head; Heterogeneity; Hispanics; Histologic; Histones; Human; Incidence; Injury to Kidney; Kidney; Kidney Diseases; Lead; Leucocytic infiltrate; Link; Liquid substance; Longitudinal Studies; Lupus; Lupus Nephritis; Maintenance; Medicine; Messenger RNA; Methods; MicroRNAs; Molecular Analysis; Mutation; Nephritis; Normal tissue morphology; Onset of illness; Organ; Pathologic Processes; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Plasma; Population; Prevalence; Process; Publications; RNA; RNA analysis; Race; Recording of previous events; Recruitment Activity; Recurrent disease; Relapse; Renal Tissue; Renal function; Research Design; Rest; Sampling; Severities; Signal Pathway; Signal Transduction; Site; Skin; Small RNA; Socioeconomic Status; Source; Staging; Stratification; Structure; Systemic Lupus Erythematosus; Tail; Techniques; Technology; Tissue Banks; Tissues; Transfer RNA; Translational Research; Transplantation; Universities; Urine; Validation; Variant; Vascular Diseases; Woman; base; biobank; candidate identification; clinical application; cohort; college; cost effective; deep sequencing; experience; insight; interest; interstitial; kidney cell; medical schools; new technology; novel; patient population; public health relevance; racial and ethnic; racial and ethnic disparities; response; systemic autoimmune disease; therapeutic development; validation studies

 DESCRIPTION (provided by applicant): Three major academic centers propose to collaborate as a combined clinical-technology site. The 2 clinical centers, NYU School of Medicine and Albert Einstein College of Medicine, have a rich and long history of commitment to SLE and together currently treat ~1,000 SLE patients. They will jointly assemble a renal phenotype-driven patient cohort comprising diverse ethnic/racial backgrounds. The Multi-Ethnic Translational Research Optimization (METRO) Lupus Consortium cohort will be leveraged to develop, standardize and validate advanced technologies to identify critical signaling pathways in tissues (renal and skin), cells and urine. Given the widespread vasculopathy characteristic of SLE, endothelial cell activation in the tubulointerstitium in lupus nephritis (LN) may be accompanied by similar activation, even in nonlesional skin. Molecular analysis of gene expression and signaling in specific subsets of renal cells may precede and predict the pathologic processes that lead to end organ damage and provide insights to deconstruct the heterogeneity of lupus in general and the histologic class of renal disease in particular. Furthermore, the faithful reflection of a relevant pathway in renal tissue by a more readily accessible tissue or fluid compartment would pave the way to early identification and treatment, critical to renal survival. Because SLE is strongly associated with racial/ethnic disparities, studies need to address whether specific biological pathways and drug targets are race-/ethnicity- dependent. Accordingly, METRO will comprise substantial numbers of Black, Hispanic, Asian, and White patients recruited at NYU (PI Buyon) and Einstein (PI Putterman). PI Dr. Thomas Tuschl at The Rockefeller University brings expertise and extensive experience in coding and non-coding RNAseq analysis and RNA diagnostic and therapeutic development. The proposal addresses 2 objectives: i) identification of candidate targets to guide novel therapy; and ii) development of non-invasive strategies to maximize early detection of LN. The former will be approached by identifying unique patterns from single-cell RNAseq (including RNA deregulation or mutation/allelic variation) in LN kidney cells (including capillary endothelial cells) compared with normal tissue/cells, and the latter by similar RNA analysis in LN matched with nonlesional skin, PBMC, and urine cellular pellet (UCP). Operationally the project is approached in sequential phases: Aim 1 (Phase 0, UH2): To establish the optimal method of renal tissue collection and single cell isolation of resident and infiltrating cells followed by poyA RNAseq, and similar application to cell populations present in nonlesional skin, PBMC, and UCP. Aim 2 (Phase I, UH2): To identify RNAseq patterns associated with different biopsy classes and compare with nonlesional skin (endothelial cells), PBMC, and UCP from the same patient. Aim 3 (Phase II, UH3): To establish whether a) the renal tissue RNAseq pattern associates with biopsy class, activity, and chronicity segregated by race/ethnicity; b) renal pattern tracks response to therapy and/or progression of renal disease in new onset or recurrent disease; and c) the pattern in skin, PBMC or UCP antedates new or relapsing kidney involvement.

 描述（由申请人提供）：三个主要学术中心提议作为一个联合临床技术中心进行合作。纽约大学医学院和阿尔伯特·爱因斯坦医学院这两个临床中心在 SLE 领域有着丰富而悠久的历史，目前总共治疗了约 1,000 名 SLE 患者。他们将共同组建一个由不同种族/种族背景组成的肾脏表型驱动的患者队列。多民族转化研究优化 (METRO) 狼疮联盟队列将用于开发、标准化和验证先进技术，以识别组织（肾脏和皮肤）、细胞和尿液中的关键信号通路。鉴于 SLE 广泛的血管病变特征，狼疮性肾炎 (LN) 肾小管间质中的内皮细胞活化可能伴随着类似的活化，即使在非病变皮肤中也是如此。对肾细胞特定亚群中基因表达和信号传导的分子分析可以先于并预测导致终末器官损伤的病理过程，并为解构一般狼疮的异质性，特别是肾病的组织学类别提供见解。此外，通过更容易接近的组织或液体隔室忠实地反映肾组织中的相关通路将为早期识别和治疗铺平道路，这对肾脏存活至关重要。由于 SLE 与种族/民族差异密切相关，因此研究需要解决特定的生物学途径和药物靶标是否具有种族/民族依赖性。因此，麦德龙将包括在纽约大学 (PI Buyon) 和爱因斯坦 (PI Putterman) 招募的大量黑人、西班牙裔、亚洲人和白人患者。洛克菲勒大学的 PI 博士 Thomas Tuschl 带来了编码和非编码 RNAseq 分析以及 RNA 诊断和治疗开发方面的专业知识和丰富经验。该提案涉及两个目标：i）确定候选靶点以指导新疗法； ii) 制定非侵入性策略以最大限度地早期检测 LN。前者将通过识别 LN 肾细胞（包括毛细血管内皮细胞）中单细胞 RNAseq（包括 RNA 失调或突变/等位基因变异）的独特模式来解决。 细胞）与正常组织/细胞进行比较，后者通过与非病变皮肤、PBMC 和尿细胞沉淀 (UCP) 相匹配的 LN 中的类似 RNA 分析来进行。在操作上，该项目分连续阶段进行： 目标 1（第 0 阶段，UH2）：建立肾组织收集和驻留细胞和浸润细胞的单细胞分离的最佳方法，然后进行 poyA RNAseq，并对非病变皮肤、PBMC 和 UCP 中存在的细胞群进行类似的应用。目标 2（第一阶段，UH2）：识别与不同活检类别相关的 RNAseq 模式，并与同一患者的非病变皮肤（内皮细胞）、PBMC 和 UCP 进行比较。目标 3（II 期，UH3）：确定 a) 肾组织 RNAseq 模式是否与按种族/民族划分的活检类别、活动性和长期性相关； b) 肾脏模式追踪新发或复发疾病中对治疗的反应和/或肾脏疾病的进展； c) 皮肤、PBMC 或 UCP 的模式早于新的或复发的肾脏受累。