Stanford Technology Accelerating Medicines Partnership Center

斯坦福大学技术加速药物合作中心

• 批准号: 10208564
• 负责人: William H Robinson
• 金额: $ 2.5万
• 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: 2014-09-24 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208564
• 关键词: Adverse event; Antibodies; Antigen Targeting; Antigens; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bar Codes; Binding; Biological; Biological Assay; Biotechnology; Blood; Blood Cells; Blood specimen; California; Cell surface; Cells; Chromatin; Collaborations; Colorado; Data Set; Databases; Dendritic Cells; Development; Disease; Disease Outcome; Drug Targeting; Epigenetic Process; Epitopes; Fc Receptor; Flare; Freezing; Funding; Future; Gene Proteins; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth Factor; High-Throughput Nucleotide Sequencing; Human; Immune; Immune Targeting; Immune response; Immune system; Immunologic Monitoring; Individual; Kidney; Leadership; Letters; Light; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediating; Medicine; Methods; Microfluidic Microchips; Mission; Monoclonal Antibodies; Multiplexed Ion Beam Imaging; National Institute of Allergy and Infectious Disease; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nature; Organ; Paper; Pathogenesis; Pathway interactions; Patients; Peptides; Phase; Pilot Projects; Plasma; Plasmablast; Population; Procedures; Process; Protein Array; Proteins; Proteomics; Reagent; Receptor Cell; Receptors, Antigen, B-Cell; Regulator Genes; Regulatory Pathway; Research; Research Personnel; Rheumatism; Rheumatoid Arthritis; Sample Size; Sampling; Signal Pathway; Signaling Molecule; Skin; Study Subject; Synovial Membrane; Systemic Lupus Erythematosus; Systems Biology; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Techniques; Technology; Tissue Sample; Tissues; Toll-like receptors; Transcript; Transposase; Universities; Validation; Yeasts; adaptive immune response; arm; base; cellular imaging; chemokine; comparative; cytokine; epigenomics; human subject; innovation; keratinocyte; kidney cell; monocyte; new technology; new therapeutic target; novel; novel marker; patient population; programs; public health relevance; receptor; recruit; repository; response; single cell analysis; single-cell RNA sequencing; statistical center; therapeutic target; tissue biomarkers; transcription factor; transcriptome sequencing; transcriptomics; virome

 DESCRIPTION (provided by applicant): The broad, long term objective of the Stanford Technology Accelerating Medicines Partnership (STAMP) Center is to serve as the leader within the RA/SLE AMP Network in the development and implementation of multiplexed mechanistic assays for AMP studies. Although we propose to focus on SLE, our methods will be used in pilot studies for RA and can be applied to any autoimmune disease. Investigators participating in this AMP proposal, and other collaborators at Stanford, have been leading innovators in the development of high-throughput genomics and proteomics technologies for studying cancer and autoimmunity. Project 1 (Steve Quake and Howard Chang) will perform transcript profiling using RNA-Seq of single cells isolated from tissue samples and blood, then separating into individual wells using Fluidigm-based microfluidics devices (C1) or FACS. The Chang lab will determine binding of transcription factors to open chromatin, repressing and/or activating transcriptional programs involving NFAT, NF¿B, RORs, IRFs, STATs, and other transcription factors. Project 2 (Garry Nolan) will employ CyTOF to study cells obtained from blood and tissue, characterizing cell surface molecules, signaling molecules, and phospho-specific epitopes in discrete cellular subsets. Upregulated transcripts from Project 1 will inform selection of CyTOF antibodies in an iterative process during the UH3 funding period. Project 3 (Bill Robinson, Mark Davis and PJ Utz) will use autoantibody profiling, FACS, repertoire-sequencing and yeast display to characterize antigen- specific B and T cells in blood and isolated from tissues. The Robinson and Davis labs will characterize the B and T cell receptor repertoire by sequencing heavy and light chain genes from FACS sorted plasmablasts, and FACS or tetramer sorted T cells, as well as cells isolated from tissue. Monoclonal antibodies will be cloned, expressed, and purified for antigen identification. Antigen targets will be discovered (Utz and Robinson) using protein arrays, which will serve as a core assay for all AMP Network Centers. Pilot projects are also proposed including plasma virome sequencing and two projects to develop and implement multiplexed ion beam imaging (MIBI). Finally, to insure availability of blood, kidney, skin, and synovium for our studies, subjects will be recruited from Stanford and the Bay Area (SLE); UCLA and Cedars- Sinai (SLE); and UCSD (RA), as well as from other AMP Centers. Integration of all assays at one AMP Center will facilitate discovery of pathways, molecules, and new drug targets.

 描述（由申请人提供）：斯坦福大学技术加速药物合作伙伴关系 (STAMP) 中心的广泛、长期目标是成为 RA/SLE AMP 网络中开发和实施 AMP 研究多重机制测定的领导者。尽管我们建议重点关注 SLE，但我们的方法将用于 RA 的试点研究，并且可以应用于任何自身免疫性疾病。开发用于研究癌症和自身免疫的高通量基因组学和蛋白质组学技术的领先创新者（Steve Quake 和 Howard Chang）将使用从组织样本和血液中分离的单细胞进行转录谱分析，然后分离成个体。 Chang 实验室将使用基于 Fluidigm 的微流体装置 (C1) 或 FACS 来确定转录因子与开放染色质的结合，从而抑制和/或激活涉及转录程序的情况。 NFAT、NF?? B、ROR、IRF、STAT 和其他转录因子项目 2（Garry Nolan）将使用 CyTOF 研究从血液和组织中获得的细胞，表征离散细胞亚群中的细胞表面分子、信号分子和磷酸化特异性表位。项目 1 的成绩单将在 UH3 资助期间的迭代过程中告知 CyTOF 抗体的选择，项目 3（Bill Robinson、Mark Davis 和 PJ Utz）将使用自身抗体。 Robinson 和 Davis 实验室将通过对 FACS 分选的重链和轻链基因进行测序来表征 B 细胞和 T 细胞受体库。浆母细胞、FACS 或四聚体分选的 T 细胞以及从组织中分离的细胞将被克隆、表达和纯化，以发现抗原靶点（Utz 和 Robinson）。还提出了使用蛋白质阵列作为所有 AMP 网络中心的核心检测的试点项目，包括血浆病毒组测序和两个开发和实施多重离子束成像 (MIBI) 的项目，以确保血液、肾脏的可用性。我们的研究中，受试者将从斯坦福大学和湾区 (SLE)、加州大学洛杉矶分校 (UCLA) 和雪松西奈分校 (SLE)、加州大学圣地亚哥分校 (RA) 以及其他 AMP 中心招募。在一个 AMP 中心整合所有检测将有助于发现通路、分子和新药物靶点。

项目成果

T Cell-Dependent Affinity Maturation and Innate Immune Pathways Differentially Drive Autoreactive B Cell Responses in Rheumatoid Arthritis.

• DOI: 10.1002/art.40578
• 发表时间: 2018-11
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Lu DR;McDavid AN;Kongpachith S;Lingampalli N;Glanville J;Ju CH;Gottardo R;Robinson WH
• 通讯作者: Robinson WH

A Comprehensive Atlas of Immunological Differences Between Humans, Mice, and Non-Human Primates.

• DOI: 10.3389/fimmu.2022.867015
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Bjornson-Hooper ZB;Fragiadakis GK;Spitzer MH;Chen H;Madhireddy D;Hu K;Lundsten K;McIlwain DR;Nolan GP
• 通讯作者: Nolan GP

Variation of Immune Cell Responses in Humans Reveals Sex-Specific Coordinated Signaling Across Cell Types.

• DOI: 10.3389/fimmu.2022.867016
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Fragiadakis GK;Bjornson-Hooper ZB;Madhireddy D;Sachs K;Chen H;McIlwain DR;Spitzer MH;Bendall SC;Nolan GP
• 通讯作者: Nolan GP