Multi-Ethnic Translational Research Optimization (METRO) Lupus Consortium

 描述（由申请人提供）：三个主要的学术中心建议作为一个联合临床技术网站进行合作。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对SLE有着丰富而悠久的承诺，目前共治疗了约1,000例SLE患者。他们将联合组成一个由不同种族/人种背景组成的肾脏表型驱动的患者队列。将利用多种族转化研究优化（METRO）狼疮联盟队列开发，标准化和验证先进技术，以确定组织（肾脏和皮肤），细胞和尿液中的关键信号通路。由于SLE的广泛血管病变特征，狼疮性肾炎（LN）肾小管上皮细胞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。对特定肾细胞亚群中基因表达和信号传导的分子分析可能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和特别是肾脏疾病的组织学类型提供见解。此外，通过更容易接近的组织或流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，这对肾存活至关重要。由于SLE与种族/民族差异密切相关，研究需要解决特定的生物学途径和药物靶点是否具有种族/民族依赖性。因此，METRO将包括在NYU（PI Buyon）和Einstein（PI Putterman）招募的大量黑人、西班牙裔、亚洲人和白色患者。洛克菲勒大学的PI博士托马斯图舍尔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。该提案解决了2个目标：i）识别候选靶点以指导新的治疗;和ii）开发非侵入性策略以最大限度地早期检测LN。前者将通过从LN肾细胞（包括毛细血管内皮细胞）中的单细胞RNAseq（包括RNA失调或突变/等位基因变异）鉴定独特模式来进行。 细胞）与正常组织/细胞进行比较，后者通过与非病变皮肤、PBMC和尿细胞团（UCP）匹配的LN中的类似RNA分析。在操作上，该项目按顺序阶段进行：目的1（阶段0，UH 2）：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，并类似地应用于存在于非病变皮肤、PBMC和UCP中的细胞群。目的2（I期，UH 2）：鉴定与不同活检分类相关的RNAseq模式，并与来自同一患者的非病变皮肤（内皮细胞）、PBMC和UCP进行比较。目的3（II期，UH 3）：确定a）肾组织RNAseq模式是否与按人种/种族划分的活检分类、活动性和慢性相关; B）肾脏模式是否跟踪新发或复发性疾病对治疗的反应和/或肾脏疾病的进展;以及c）皮肤、PBMC或UCP中的模式是否先于新发或复发性肾脏受累。

 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.