Translational Center of Molecular Profiling in Preclinical and Established Lupus (COMPEL)

临床前和已确诊狼疮分子分析转化中心 (COMPEL)

• 批准号: 9766075
• 负责人: Jill P Buyon
• 金额: $ 134万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766075
• 关键词: Abnormal Cell; Address; Alleles; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Attention; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Bacteria; Basic Science; Benign; Bioinformatics; Biological Sciences; Blood; CD4 Positive T Lymphocytes; Caring; Cellular biology; Clinical; Clinical Management; Clonal Expansion; Clone Cells; Cloning; Collaborations; Complex; Computational Science; Culture-independent methods; DNA; Databases; Deoxyribonucleases; Development; Disease; Environmental Risk Factor; Exanthema; Family Study; Flare; Genes; Genetic; Genetic Variation; Gnotobiotic; Goals; Heart Diseases; Hospitals; Human; Immune; Immune response; Immune system; Immunoglobulin A; Immunoglobulin G; Individual; Inflammatory; Injury; Intestines; Investigation; Kidney; Laboratories; Lupus; Mediating; Medical; Medicine; Modeling; Molecular; Molecular Profiling; Mucosal Immunity; Mus; Musculoskeletal; Nature; Neonatal lupus erythematosus; New York; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Penetrance; Persons; Phenotype; Predisposition; Prevention; Receptors, Antigen, B-Cell; Registries; Reporting; Research; Research Personnel; Research Project Grants; Resources; Rest; Ribosomal RNA; Risk; Role; Sampling; Science; Scientist; Severities; Specificity; Sum; Surveys; Susceptibility Gene; Systemic Lupus Erythematosus; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Universities; Widespread Disease; Woman; Work; arthropathies; bacterial community; base; biobank; cohort; commensal microbes; cross reactivity; ds-DNA; ethnic diversity; genome wide association study; in vivo; insight; medical schools; microbial; microbiome; offspring; pathobiont; peripheral blood; pre-clinical; programs; racial and ethnic; racial diversity; response; statistics; translational study

NYU School of Medicine and collaborating clinical and basic investigators in Medicine and Pathology propose to establish the Translational Center of Molecular Profiling in Preclinical and Established Lupus (COMPEL) comprising 3 Projects, 2 Research Cores, and an Administrative Core. The overarching goal is to elucidate the mechanisms by which Systemic Lupus Erythematosus (SLE), a prototypic yet clinically and immuno- molecularly heterogeneous autoimmune disease, is initiated and perpetuated. COMPEL leverages a) a unique cohort of asymptomatic women presenting with breakdown in B cell tolerance identified because of neonatal lupus (NL) in an offspring (Research Registry for Neonatal Lupus, RRNL) and b) a robustly phenotyped cohort of established SLE patients spanning diverse racial backgrounds and with a high penetrance of serious illness (NYU Cohort). Project 1 profiles anti-Ro preclinical and clinical autoimmunity to identify blueprints of an immune system that remains preclinical, and in individuals who have progressed to overt disease. The approach rests on identifying associations between host genetics, the microbiome, and the phenotype of CD4+ T cells, which constitute an immune triumvirate of T cells, antigen-presenting cells with an MHC II-defined specificity towards particular microbial taxa, and B cells. Project 2 explores microbiome pathobionts and SLE pathogenesis to understand how specific candidate pathobiont bacterial isolates contribute to overt SLE disease and flares, and to peripheral blood expansion of disease-associated B cell clones. Human intestinal IgA responses can be both specific for in vivo eliciting bacteria, and often cross-reactive with self-antigens. Yet, the gut-associated B cell response has not been investigated in SLE as a driver of autoimmune disease. Project 3 focuses on DNASE1L3, a unique secreted DNase that is essential for protection against SLE. We have shown that DNASE1L3 digests DNA in circulating microparticles and antibody (Ab) reactivity to microparticle antigens is frequently detected in SLE. The project will explore Ab responses to DNASE1L3- sensitive microparticle antigens in preclinical and established SLE patients; molecularly characterize these antigens and test DNASE1L3 as a therapeutic. The Research Technology Core brings advanced technology for NGS applications of large scale autoAb gene repertoire analyses from human B cell samples and will sort intestinal IgA-coated bacteria profiled by 16S rRNA microbiome surveys. The Clinical Core comprises the database (REDCap) and biobank (Freezerworks) of 3 cohorts (RRNL, NYU Lupus Cohort, healthy controls) to facilitate translational studies. The Administrative Core supports organizational, financial and reporting activities. The analytic team brings expertise in biostatics, genetic statistics, bioinformatics and computational science. External advisors covering translational SLE, the microbiome, T cell biology and mucosal immunity, and 2 lay persons with ties to NL, will provide overall review and with COMPEL select Pilot/Feasibility Projects to leverage program resources and expand thematic objectives.

纽约大学医学院和医学和病理学领域的临床和基础研究人员合作提出 建立临床前和已确诊狼疮分子分析转化中心 (COMPEL) 包括 3 个项目、2 个研究核心和一个行政核心。总体目标是阐明 系统性红斑狼疮（SLE）是一种典型的临床和免疫性疾病，其机制 分子异质性自身免疫性疾病的发生和延续。 COMPEL 利用 a) 独特的 一组无症状妇女由于新生儿原因而出现 B 细胞耐受性下降 后代狼疮 (NL)（新生儿狼疮研究登记处，RRNL）和 b) 稳健表型队列 跨越不同种族背景且患有严重疾病的高外显率的已确诊的 SLE 患者 （纽约大学队列）。项目 1 分析抗 Ro 临床前和临床自身免疫，以确定抗 Ro 的蓝图 仍处于临床前状态的免疫系统，以及已进展为明显疾病的个体的免疫系统。这 该方法依赖于确定宿主遗传学、微生物组和 CD4+ 表型之间的关联 T 细胞，构成 T 细胞的免疫三巨头，具有 MHC II 定义的抗原呈递细胞 针对特定微生物类群和 B 细胞的特异性。项目 2 探索微生物组病原体和 SLE 发病机制，以了解特定候选致病细菌分离株如何导致明显的 SLE 疾病和耀斑，以及与疾病相关的 B 细胞克隆的外周血扩增。人体肠道 IgA 反应可以是体内引发细菌特异性的，并且通常与自身抗原发生交叉反应。然而， 肠道相关 B 细胞反应尚未在 SLE 中作为自身免疫性疾病的驱动因素进行研究。 项目 3 重点关注 DNASE1L3，这是一种独特的分泌型 DNase，对于预防 SLE 至关重要。我们 已经表明 DNASE1L3 消化循环微粒中的 DNA，并且抗体 (Ab) 与 微粒抗原在 SLE 中经常被检测到。该项目将探索 DNASE1L3 的抗体反应 - 临床前和已确诊的 SLE 患者的敏感微粒抗原；分子表征这些 抗原并测试 DNASE1L3 作为治疗剂。研究技术核心带来先进技术 用于从人类 B 细胞样本中进行大规模 autoAb 基因库分析的 NGS 应用，并将进行分类 通过 16S rRNA 微生物组调查分析肠道 IgA 包被细菌。临床核心包括 3 个队列（RRNL、纽约大学狼疮队列、健康对照）的数据库 (REDCap) 和生物库 (Freezerworks) 促进转化研究。行政核心支持组织、财务和报告 活动。分析团队带来生物统计学、遗传统计学、生物信息学和计算方面的专业知识 科学。外部顾问涵盖转化 SLE、微生物组、T 细胞生物学和粘膜免疫， 和 2 名与 NL 有联系的外行人士将提供全面审查，并与 COMPEL 一起选择试点/可行性项目 利用计划资源并扩大专题目标。