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: 10004495
• 负责人: Jill P Buyon
• 金额: $ 131.91万
• 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/10004495
• 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; 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; genetic manipulation; 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; tissue injury; translational study; 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; 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; genetic manipulation; 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; tissue injury; 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.

纽约大学医学和合作医学和病理学的临床和基本研究人员提出 在临床前和已建立的狼疮（cerpel）中建立分子分析的翻译中心 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 全身性红斑狼疮（SLE）的机制，一种原型但临床和免疫的机制 启动并永久存在分子异质自身免疫性疾病。强迫利用a）独特 由于新生儿而识别出的B细胞耐受性分解的无症状妇女的队列 狼疮（NL）的后代（新生儿狼疮的研究注册中心，rrnl）和b）强大的表型队列 涵盖各种种族背景和严重疾病的既有种族背景的既定SLE患者 （NYU队列）。项目1介绍抗临床前和临床自身免疫性，以识别 仍然是临床前的免疫系统，以及已经发展为明显疾病的个体。这 方法取决于识别宿主遗传学，微生物组和CD4+表型之间的关联 T细胞构成T细胞的免疫triumvirate，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 发病机理，了解特定候选病原体细菌分离株如何有助于明显的SLE 疾病和耀斑，以及与疾病相关的B细胞克隆的外周血扩展。人类肠道 IgA反应既可以特异性地用于体内引起细菌，又可以与自我抗原交叉反应。然而， 在SLE中，尚未研究与肠道相关的B细胞反应作为自身免疫性疾病的驱动因素。 项目3专注于DNASE1L3，这是一种独特的分泌DNase，对于防止SLE至关重要。我们 已经表明DNase1L3在循环微粒和抗体（AB）反应性中消化DNA 在SLE中经常检测到微粒抗原。该项目将探索AB对DNASE1L3-的反应 临床前和已建立的SLE患者的敏感微粒抗原；分子表征这些 抗原和测试DNase1L3作为治疗性。研究技术核心带来了先进的技术 对于大规模的NGS应用，来自人类B细胞样品的大规模自动基因库分析 由16S rRNA微生物组调查介绍了肠道IgA涂层的细菌。临床核心包括 3个队列的数据库（REDCAP）和生物库（冰柜）（RRNL，Nyu Lupus队列，健康对照） 促进翻译研究。行政核心支持组织，财务和报告 活动。分析团队具有生物统计学，遗传统计，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个与NL有联系的外行人将提供整体审查，并强迫精选的飞行员/可行性项目 利用计划资源并扩大主题目标。