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.

纽约大学医学院和合作的临床和基础医学和病理学研究人员提出 在临床前和已确诊的狼疮中建立分子图谱翻译中心(COMPELL) 包括3个项目、2个研究核心和1个行政核心。首要目标是阐明 系统性红斑狼疮(SLE)是一种典型的临床和免疫学疾病。 分子异质性的自身免疫性疾病是始发并持续存在的。强制利用a)独特的 因新生儿而出现B细胞耐受性崩溃的无症状妇女队列 后代中的狼疮(NL)(新生儿狼疮研究登记，RRNL)和b)一个强健的表型队列 已确诊的SLE患者跨越不同种族背景和严重疾病的高外显率 (纽约大学队列)。项目1介绍抗Ro临床前和临床自身免疫以确定一个蓝图 仍处于临床前状态的免疫系统，以及已进展为显性疾病的个体。这个 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，它构成了T细胞的免疫三重奏，抗原提呈细胞具有MHC II定义 对特定微生物类群和B细胞的特异性。项目2探索微生物组致病细菌和系统性红斑狼疮 发病机制以了解特定的候选致病细菌分离株如何对显性SLE起作用 疾病和耀斑，以及与疾病相关的B细胞克隆的外周血液扩张。人体肠道 免疫球蛋白反应既可以是体内激发细菌的特异性反应，也可以与自身抗原交叉反应。然而， 在系统性红斑狼疮中，肠道相关的B细胞反应尚未被作为自身免疫性疾病的驱动因素进行研究。 项目3的重点是DNASE1L3，这是一种独特的分泌DNA酶，对预防SLE至关重要。我们 已表明DNASE1L3消化循环微粒中的DNA和抗体(Ab)对 在系统性红斑狼疮中经常检测到微粒抗原。该项目将探索对DNASE1L3的抗体反应- 临床前和已确诊的SLE患者中的敏感微粒抗原；分子特征 并检测DNASE1L3作为一种治疗方法。研究技术核心带来先进技术 对于NGS应用大规模的人类B细胞样本中的自体抗体基因库分析，并将进行排序 16S rRNA微生物组分析肠道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) 促进翻译研究。行政核心支持组织、财务和报告 活动。分析小组带来了生物静力学、遗传统计学、生物信息学和计算方面的专业知识 科学。翻译类系统性红斑狼疮、微生物组、T细胞生物学和粘膜免疫的外部顾问， 和2名与NL有联系的非专业人员，将提供全面审查，并强制选择试点/可行性项目 利用计划资源，扩大主题目标。