Core C: Subtractive Single Nucleus Seq and Spatial Multi-omics Core

核心 C：减法单核测序和空间多组学核心

• 批准号: 10643432
• 负责人: Le Zhang
• 金额: $ 29.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643432
• 关键词: ATAC-seq; Animal Model; Autoimmune Diseases; Autoimmunity; Bar Codes; Biological Assay; Biological Process; Brain; Cell Nucleus; Cell physiology; Cells; Chromatin; Clinical; Computational Biology; Data; Data Set; Detection; Disease; Disease model; Epigenetic Process; Experimental Models; Foundations; Freezing; Generations; Genes; Genetic Transcription; Genomics; Glioblastoma; Goals; Grant; Health; Human; Image; Immune; Immune response; Immune signaling; Immunity; Immunobiology; Immunologics; Inflammasome; Inflammation; Investigation; Joints; Knockout Mice; Ligands; Malignant Neoplasms; Maps; Methods; Microfluidics; Microglia; Modeling; Molecular Profiling; Molecular Target; Morphology; Multiple Sclerosis; Mus; Myelogenous; Myeloid Cells; Outcome; PD-1/PD-L1; Pathway Analysis; Pathway interactions; Preparation; Process; Program Research Project Grants; Proteomics; Regulatory T-Lymphocyte; Reproducibility; Research; Research Personnel; Research Project Grants; Resolution; Role; Sampling; Services; Signal Pathway; Signal Transduction; Slide; Structure; Surface; System; T-Lymphocyte; Technology; Therapeutic Uses; Tissues; Tumor-Infiltrating Lymphocytes; Universities; Work; autoreactive T cell; cell type; computing resources; data integration; epigenomics; human disease; human model; human tissue; immune function; insight; mouse model; multiple omics; multiple sclerosis patient; neuroinflammation; new technology; new therapeutic target; novel; programmed cell death protein 1; receptor; single cell analysis; single nucleus RNA-sequencing; single-cell RNA sequencing; therapeutic target; tissue fixing; tissue preparation; tool; transcriptomic profiling; transcriptomics

PROJECT SUMMARY – CORE C Efficient and reproducible detection of immune cell states is paramount to our understanding of the immune responses in the context of health and disease, such as cancer and autoimmunity. Immune function is highly dependent upon costimulatory signals where their role has become apparent in the study of tumor infiltrating lymphocytes with PD-1/PD-L1 expression, as well as in autoimmune disease particularly with activation of autoreactive T cells and costimulatory receptor CD226 and its ligand CD155 which is shared with TIGIT. Achieving a mechanistic understanding by which PD-1/PD-L1 and TIGIT/CD155 axes regulate T cell and myeloid cell function will enable refinement of the therapeutic use and target of these costimulatory pathways. The Single Cell and Spatial Multi-omics Core (Core C) at Yale University will provide support for novel transcriptional, epigenetic, and spatial profiling of single cells as well as enriched immune cell types across all three projects of the Program Project Grant. Our core has established systematic pipelines for processing single cell RNA-seq and ATAC-seq from low-input samples, from single cells or single nuclei, as well as for spatial transcriptomics using DBiT-seq, a single cell spatial technology newly developed at Yale which will be used in both experimental models and in human tissues across the three projects. This core provides capabilities and a pipeline for the preparation, sequencing and single cell analysis and data integration across species. Our experimental and computational resource will facilitate (1) the investigations of immunity in mouse models that are deficient for TIGIT, PD1, or both, (2) the characterization of cells or nuclei or sections human tissues from patients with multiple sclerosis and glioblastoma, and (3) the single cell, integrative analysis of all data generated in Projects 1-3. Overall, the outcome will be a better understanding of co-stimulatory and co-inhibitory mechanisms, and its function in regulating inflammasome activation in T cells and myeloid cells in human diseases and disease models. This may potentially lead to new avenues for therapy for autoimmunity and cancer.

项目概要-核心C 免疫细胞状态的有效和可重复的检测对于我们理解免疫系统至关重要。 在健康和疾病的背景下，如癌症和自身免疫反应。免疫功能 高度依赖于共刺激信号，其中它们的作用在肿瘤的研究中变得明显 具有PD-1/PD-L1表达的浸润淋巴细胞，以及自身免疫性疾病，特别是 激活自身反应性T细胞和共刺激受体CD 226及其配体CD 155， 关于TIGIT实现PD-1/PD-L1和TIGIT/CD 155轴调节T细胞的机制理解 细胞和骨髓细胞的功能将使得这些共刺激因子的治疗用途和靶点的改进成为可能。 途径。耶鲁大学的单细胞和空间多组学核心（Core C）将为新的研究提供支持。 转录、表观遗传和空间分析单细胞以及所有免疫细胞类型的富集 计划项目补助金的三个项目。我们的核心已经建立了系统的管道处理单 细胞RNA-seq和ATAC-seq来自低输入样品，来自单细胞或单细胞核，以及用于空间 使用DBiT-seq的转录组学，这是耶鲁大学新开发的单细胞空间技术，将用于 这三个项目的实验模型和人体组织。该核心提供了各种功能， 用于制备、测序和单细胞分析以及跨物种数据集成的管道。我们 实验和计算资源将促进（1）在小鼠模型中的免疫研究， 缺乏TIGIT、PD 1或两者，（2）来自人组织的细胞或细胞核或切片的表征 多发性硬化症和胶质母细胞瘤患者，以及（3）单细胞，综合分析所有数据生成 项目1-3。总的来说，结果将是更好地理解共刺激和共抑制 机制及其在调节人T细胞和骨髓细胞中炎性小体活化中的作用 疾病和疾病模型。这可能潜在地导致用于治疗自身免疫性的新途径， 癌