Multi-Ethnic Translational Research Optimization (METRO) Lupus Consortium

 描述(由申请者提供)：三个主要学术中心提出合作，作为一个联合的临床技术网站。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系统性红斑狼疮有着丰富而悠久的承诺，目前总共治疗了约1000名系统性红斑狼疮患者。他们将共同组建一个由肾脏表型驱动的患者队列，其中包括不同的民族/种族背景。多民族翻译研究优化(Metro)狼疮联盟队列将被用来开发、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。鉴于系统性红斑狼疮广泛的血管病变特点，狼疮性肾炎(LN)肾小管间质内皮细胞的激活可能伴随着类似的激活，甚至在非皮损皮肤中也是如此。对特定肾细胞亚群中基因表达和信号的分子分析可能先于并预测导致终末器官损害的病理过程，并为解构狼疮的异质性，特别是肾脏疾病的组织学类别提供见解。此外，通过更容易接触到的组织或液体腔忠实地反映肾组织中的相关途径，将为早期识别和治疗铺平道路，这对肾脏生存至关重要。由于系统性红斑狼疮与种族/民族差异密切相关，研究需要解决特定的生物途径和药物靶点是否与种族/民族有关。因此，Metro将包括大量在纽约大学(Pi Buyon)和爱因斯坦(Pi Putterman)招募的黑人、西班牙裔、亚洲和白人患者。洛克菲勒大学的Pi Thomas Tuschl博士在编码和非编码RNAseq分析以及RNA诊断和治疗开发方面带来了专业知识和丰富的经验。该提案涉及两个目标：i)确定候选靶点以指导新的治疗；以及ii)开发非侵入性策略，以最大限度地早期发现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的独特模式(包括RNA去调控或突变/等位基因变异)来实现 细胞)与正常组织/细胞进行比较，后者与非皮损皮肤、外周血单个核细胞和尿细胞小球(UCP)相匹配的LN进行相似的RNA分析。在操作上，该项目按顺序进行：目标1(0期，UH2)：建立POYA RNAseq的肾组织采集和常驻细胞和浸润性细胞的单细胞分离的最佳方法，并类似地应用于非皮损皮肤、PBMC和UCP中的细胞群。目的2(阶段I，UH2)：确定与不同活检类型相关的RNAseq模式，并与同一患者的非皮损皮肤(内皮细胞)、PBMC和UCP进行比较。目的3(第二阶段，UH3)：确定a)肾组织RNAseq模式是否与按种族/民族分离的活检类别、活动性和慢性化有关；b)肾脏模式跟踪新发或复发疾病对治疗和/或进展的反应；c)皮肤、PBMC或UCP的模式先于新发或复发的肾脏受累。

 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.