Advanced Spatial Analysis Core

高级空间分析核心

• 批准号: 10619300
• 负责人: JACOB D ESTES
• 金额: $ 50.52万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619300
• 关键词: Adopted; Antigen-Antibody Complex; Atlases; B-Lymphocytes; Bioinformatics; Biology; Biometry; Blood; CCRL2 gene; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Complex; Computer Models; Cytokine Signaling; Data; Data Analyses; Data Set; Development; Disease; Flow Cytometry; Gene Expression; Gene Expression Profile; Generations; Genetic Transcription; HIV; Histopathology; Immune; Immune response; Immune system; Immunization Programs; Immunofluorescence Immunologic; Immunohistochemistry; Immunologics; Immunology; In Situ; In Situ Hybridization; Infection; Intercept; Interleukin-15; Link; Lymphoid Tissue; Macaca mulatta; Maps; Mediating; Microscopy; Modeling; Multiomic Data; Nature; Neighborhoods; Output; Pathogenesis; Pathway interactions; Pattern; Periodicity; Phenotype; Population; Process; Residual state; Resolution; SIV; SIV Vaccines; Signal Transduction; System; T cell response; T-Lymphocyte; Tissues; Vaccinated; Vaccines; Viral; Viral Genes; Viral reservoir; Virus; Work; cell type; high dimensionality; immunoregulation; in vivo; insight; nano-string; novel; programs; protein expression; single cell analysis; tool; transcriptomics; transmission process; vaccine efficacy; vector; virology; whole slide imaging

CORE C PROJECT SUMMARY A comprehensive understanding of the dynamic interplay between immune responses and the virus within the spatial context of infected tissues after SIV challenge will be essential to dissect the mechanisms responsible for initiating and maintaining 68-1 RhCMV/SIV vaccine-mediated SIV replication arrest efficacy and to define the basis of the ability of MHC-E-restricted CD8+ T cells, but not MHC-Ia or MHC-II-restricted CD8+ T cells, to mediate this type of protection. In order to capture the dynamic breadth and nature of the complex immunologic processes within tissues in early primary SIV infection and to unravel the mechanisms of RhCMV/SIV vaccine efficacy, the Advanced Spatial Analysis Core (Core C) will utilize a battery of novel high-dimensional spatial approaches to elucidate 1) the state of the virus, including identity of infected cells, viral gene and protein expression, and infected cell transcriptional patterns (S.A.1), and 2) essential immune cell profiles, including phenotypes, subsets, activation/immunoregulatory states, cytokine signaling, effector functions and transcriptomic landscapes (S.A.2) that will define the virology and immunology of established replication arrest (Project 1) and will distinguish the in vivo immune interception of primary SIV infection by protective MHC-E-restricted CD8+ T cells from non-protective MHC-E-, MHC-Ia- or MHC-II-restricted CD8+ T cells elicited by differentially programmed RhCMV/SIV vectors, or MHC-Ia-restricted CD8+ T cell responses elicited by a conventional prime- boost vaccine (Project 2). The Core will interrogate spatial virologic, phenotypic, and transcriptomic data on single-cells, populations, and cell neighborhoods in tissues associated with SIV transmission using high- dimensional RNAscope/DNAscope, PANINI-CODEX spatial phenotyping, and GeoMx DSP and CosMx SMI spatial transcriptomics platforms, and will link spatial data sets with bulk and single-cell transcriptomic data sets on matched tissues (and blood), to comprehensively define gene expression signatures, networks and immunological responses (but with additional spatial context) associated with RhCMV/SIV vaccine-mediated SIV replication arrest. Core D will apply cutting edge bioinformatics approaches to model the functional outputs and inform the mechanisms of action by which RhCMV/SIV vaccination programs the immune response for protection against SIV infection. Core C is directed by Dr. Jacob Estes, who will work closely with Core D, Drs. Michael Gale, Jr. and Ben Bimber, and with Core A, statistician Dr. Paul Edlefsen, to provide consistent, high-quality functional multi-omics data generation, integrated data analysis, biostatistical analyses and computational modeling in support of the advanced spatial analysis being performed for this scientific program. 1

核心C项目摘要 对免疫反应与病毒之间动态相互作用的全面理解 SIV挑战后感染组织的空间环境对于剖析负责的机制至关重要 启动和维持68-1 RHCMV/SIV疫苗介导的SIV复制阻滞功效并定义 MHC-E限制的CD8+ T细胞的能力，而不是MHC-IA或MHC-II限制的CD8+ T细胞的能力，可以介导 这种类型的保护。为了捕获复杂免疫过程的动态广度和性质 早期原发性SIV感染的组织内部，并阐明RHCMV/SIV疫苗功效的机制，即 高级空间分析核心（核心C）将利用一系列新型的高维空间方法 阐明1）病毒状态，包括感染细胞的身份，病毒基因和蛋白质表达，以及 受感染的细胞转录模式（S.A.1）和2）必需的免疫细胞谱，包括表型， 子集，激活/免疫调节状态，细胞因子信号传导，效应子功能和转录组 景观（S.A.2）将定义既定复制逮捕的病毒学和免疫学（项目1）和 将通过保护性MHC-E限制的CD8+ T区分原发SIV感染的体内免疫截距 来自非保护MHC-E-，MHC-IA-或MHC-II限制的CD8+ T细胞的细胞，这些细胞由差异化引起 编程的RHCMV/SIV载体或MHC-IA限制的CD8+ T细胞反应，该反应由常规质量 - 增强疫苗（项目2）。核心将询问有关空间病毒学，表型和转录组的核心数据 使用高 - 尺寸rnascope/dnaScope，panini-codex空间表型以及GEOMX DSP和COSMX SMI 空间转录组学平台，并将将空间数据集与批量和单细胞转录组数据集联系起来 在匹配的组织（和血液）上，全面定义基因表达特征，网络和 与RHCMV/SIV疫苗介导的SIV相关的免疫反应（但具有其他空间环境） 复制逮捕。核心D将采用尖端生物信息学方法来对功能输出进行建模和 告知RHCMV/SIV疫苗接种计划免疫反应以保护的作用机制 反对SIV感染。 Core C由Jacob Estes博士执导，他将与Drs Core D密切合作。迈克尔 小盖尔（Gale，Jr。）和本·比姆伯（Ben Bimber），以及统计学家保罗·埃德尔夫森（Paul Edlefsen）博士，提供一致，高质量的 功能多摩斯数据生成，集成数据分析，生物统计分析和计算 建模以支持为该科学计划执行的高级空间分析。 1