ACE: Autoimmunity Center of Excellence (ACE) at Stanford

ACE：斯坦福大学自身免疫卓越中心 (ACE)

• 批准号: 8680545
• 负责人: PAUL JOSEPH UTZ
• 金额: $ 74.35万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680545
• 关键词: Adult; Adverse event; Antibodies; Antigen-Antibody Complex; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Basic Science; Biological Assay; Biological Markers; Blood Cells; Blood specimen; Childhood; Chronic Childhood Arthritis; Clinical Trials; Development; Diagnosis; Disease; Disease Outcome; Fc Receptor; Flare; Funding; Future; Goals; Human; Immunologic Monitoring; Immunologic Receptors; Mediating; Methods; NF-kappa B; Nature; Pathogenesis; Pathogenicity; Patients; Peptides; Proteins; Receptor Signaling; Receptors, Antigen, B-Cell; Research; Research Personnel; Rheumatism; Rheumatoid Arthritis; Serum; Signal Pathway; Site; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Technology; Testing; Toll-like receptors; Transposase; Treatment Efficacy; XCL1 gene; autoreactive B cell; autoreactive T cell; base; cell type; cytokine; epigenomics; flexibility; improved; monocyte; new technology; novel; outcome forecast; receptor; repository; response

DESCRIPTION (provided by applicant): The Broad, Long Term Objective of the Stanford ACE is to serve as the leader within the ACE network in the development, implementation, and dissemination of multiplexed mechanistic assays for ACE trials. This proposal will develop 4 creative and novel techniques for mechanistic studies that can be transferred to our Human Immune Monitoring Center (HIMC, ACE Core B). As proof-of-principle, we propose to study B cells and antibodies in Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and Systemic Juvenile Idiopathic Arthritis (SJIA). Nevertheless, our new techniques can be used to study any autoimmune disease, and many cell types including monocytes and T lymphocytes. This flexibility should set the Stanford ACE apart from all other ACE sites. Most autoimmune diseases are associated with serum autoantibodies used to assist with diagnosis and prognostication. Critical questions remain in the field regarding the nature of the response to self. Do autoreactive B and T cells cause disease? Are autoantibodies and immune complexes (ICs) directly pathogenic, and if so which antigens drive disease? The overarching goal of the Stanford ACE proposal is to test the hypothesis that a subset of ICs are pathogenic in adult and pediatric rheumatic diseases, and that the mechanism(s) underlying their pathogenicity include cytokines, innate immune receptors (Fc receptors, Toll Like Receptors, TLRs), and signaling pathways mediated by JAK/STAT, NFKB, RORs, NFAT, IRFs, and other transcriptional regulators. We will take advantage of a rich repository of well characterized blood samples derived from patients with SLE, RA, and SJIA. We will test the hypothesis through further development of creative new technologies including protein and peptide arrays, B cell receptor sequencing, CyTOF, and an epigenomic assay called ATAC-Seq. We will disseminate assays to HIMC (ACE Core B) and other ACE sites, and will (i.) expand application of the technologies to additional human autoimmune diseases during the ACE funding period, (ii.) collaborate with other ACE investigators on their basic science projects, and (iii.) incorporate all 4 assays and Cores into the ACE Shared Research Agenda as mechanistic core assays for clinical trials.

描述（由申请人提供）：斯坦福ACE的广泛，长期目标是在开发，实施和传播ACE试验的多路复用机械测定法中作为ACE网络中的领导者。该提案将开发4种创意和新颖的技巧，用于机械研究，可以将其转移到我们的人类免疫监测中心（HIMC，ACE Core B）。作为原理证明，我们建议研究全身性红斑狼疮（SLE），类风湿关节炎（RA）和全身少年特发性关节炎（SJIA）中的B细胞和抗体。然而，我们的新技术可用于研究任何自身免疫性疾病，以及许多细胞类型，包括单核细胞和T淋巴细胞。这种灵活性应该使斯坦福王牌与所有其他ACE网站区分开。大多数自身免疫性疾病与用于诊断和预后的血清自身抗体有关。关于自我反应的性质，关键问题仍然存在。自动反应性B和T细胞会引起疾病吗？自身抗体和免疫复合物（ICS）是否直接致病，如果是，哪种抗原驱动疾病？ The overarching goal of the Stanford ACE proposal is to test the hypothesis that a subset of ICs are pathogenic in adult and pediatric rheumatic diseases, and that the mechanism(s) underlying their pathogenicity include cytokines, innate immune receptors (Fc receptors, Toll Like Receptors, TLRs), and signaling pathways mediated by JAK/STAT, NFKB, RORs, NFAT, IRF和其他转录调节器。我们将利用富含SLE，RA和SJIA患者的表征性良好的血液样本的存储库。我们将通过进一步开发创造性新技术（包括蛋白质和肽阵列，B细胞受体测序，细胞胞丝）和一种称为ATAC-SEQ的表观基因组分析来检验假设。我们将向HIMC（ACE Core B）和其他ACE网站进行分配测定，并将（即）在ACE资助期间将技术应用于其他人类自身免疫性疾病，（II。）与其他ACE研究人员在其基本科学项目上合作，（III。