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的临床和基础研究人员合作， 建立临床前和确诊狼疮分子谱转化中心（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）是一种原型的，但在临床上和免疫学上， 分子异质性自身免疫性疾病，是发起和延续。COMPEL利用a）独特的 一组无症状女性，由于新生儿感染而导致B细胞耐受性下降 （新生儿狼疮研究登记处，RRNL）和B）稳健表型队列 不同种族背景的确诊SLE患者中， (NYU队列）。项目1描述抗Ro临床前和临床自身免疫，以确定抗Ro抗体的蓝图。 免疫系统仍然是临床前，并在个人谁已经发展到明显的疾病。的 这种方法依赖于确定宿主遗传学、微生物组和CD4+细胞表型之间的关联。 T细胞，其构成T细胞的免疫三巨头，具有MHC II定义的抗原呈递细胞， 对特定微生物分类群和B细胞的特异性。项目2探索微生物组致病菌和SLE 发病机制，以了解特定的候选致病菌分离株如何导致明显的SLE 疾病和突发，以及疾病相关B细胞克隆的外周血扩增。人肠 IgA应答可以是体内引发细菌特异性的，并且通常与自身抗原交叉反应。然而， 肠相关B细胞应答在SLE中作为自身免疫性疾病的驱动因素尚未被研究。 项目3的重点是DNASE1L3，一种独特的分泌型DNA酶，对预防SLE至关重要。我们 已经表明，DNASE1L3抑制循环微粒中的DNA和抗体（Ab）对 微粒抗原经常在SLE中检测到。该项目将探索抗体对DNASE1L3的反应- 临床前和确定的SLE患者中的敏感微粒抗原; 抗原和测试DNASE1L3作为治疗剂。研究技术核心带来了先进的技术 对于NGS应用，从人B细胞样品中进行大规模autoAb基因库分析，并将 通过16S rRNA微生物组调查分析的肠道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 活动分析团队带来了生物统计学，遗传统计学，生物信息学和计算 科学外部顾问涵盖翻译SLE，微生物组，T细胞生物学和粘膜免疫， 和2名与NL有联系的非专业人员，将提供全面审查，并与COMPEL一起选择试点/可行性项目 利用项目资源，扩大主题目标。