ACE: Autoimmunity Center of Excellence (ACE) at Stanford

ACE：斯坦福大学自身免疫卓越中心 (ACE)

基本信息

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
项目类别：
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

项目摘要

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）：斯坦福大学 ACE 的广泛、长期目标是成为 ACE 网络内开发、实施和传播 ACE 试验多重机制测定的领导者。该提案将开发 4 种用于机械研究的创造性和新颖的技术，这些技术可以转移到我们的人类免疫监测中心（HIMC，ACE Core B）。作为原理验证，我们建议研究系统性红斑狼疮 (SLE)、类风湿性关节炎 (RA) 和系统性幼年特发性关节炎 (SJIA) 中的 B 细胞和抗体。尽管如此，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 ACE 区别于所有其他 ACE 站点。大多数自身免疫性疾病与用于协助诊断和预测的血清自身抗体有关。关于自我反应的本质，这一领域仍然存在关键问题。自身反应性 B 细胞和 T 细胞会导致疾病吗？自身抗体和免疫复合物 (IC) 是否直接致病？如果是，哪些抗原会导致疾病？斯坦福大学 ACE 提案的总体目标是检验以下假设：IC 的一部分对成人和儿童风湿病具有致病性，其致病机制包括细胞因子、先天免疫受体（Fc 受体、Toll 样受体）、TLR）以及由 JAK/STAT、NFKB、ROR、NFAT、IRF 和其他转录调节因子介导的信号通路。我们将利用来自 SLE、RA 和 SJIA 患者的丰富的特征明确的血液样本库。我们将通过进一步开发创造性的新技术来检验这一假设，包括蛋白质和肽阵列、B 细胞受体测序、CyTOF 以及称为 ATAC-Seq 的表观基因组测定。我们将向 HIMC（ACE Core B）和其他 ACE 站点传播检测方法，并将 (i.) 在 ACE 资助期间将这些技术的应用范围扩大到其他人类自身免疫性疾病，(ii.) 与其他 ACE 研究人员就其基础研究进行合作科学项目，以及 (iii.) 将所有 4 种检测方法和核心纳入 ACE 共享研究议程，作为临床试验的机械核心检测方法。