Project 2: Systems biology analyses of RHCMV/SIV and IL-15 mechanisms of immune programming

项目2：RHCMV/SIV和IL-15免疫编程机制的系统生物学分析

• 批准号: 10723640
• 负责人: Michael Gale
• 金额: $ 32.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723640
• 关键词: Acute; Address; Bioinformatics; Blood; CD8-Positive T-Lymphocytes; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Computer Analysis; Coupled; Cytomegalovirus; Data Set; Gene Expression; Genes; Goals; Gut associated lymphoid tissue; HIV Antigens; HIV vaccine; Human; Immune; Immune response; Immune signaling; Immunity; In Vitro; Infection; Inflammatory; Intercept; Interferons; Interleukin-15; Knowledge; Link; Lymphoid Tissue; Macaca mulatta; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mucous Membrane; Pathogenicity; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Production; Research Design; Rhesus; SIV; SIV Vaccines; Signal Pathway; Signal Transduction; Site; Statistical Data Interpretation; System; Systems Biology; T-Lymphocyte; Tissues; Translating; Vaccinated; Vaccination; Vaccines; Viral; Viral Antigens; Virus; Virus Diseases; Whole Blood; Work; cell type; cohort; functional genomics; gene network; genomic data; immune activation; in vivo; lymph nodes; monocyte; nano-string; predictive marker; predictive signature; programs; response; single-cell RNA sequencing; success; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; treatment response; vaccine efficacy; vaccine response; vaccinology; vector; vector-based vaccine

Project 2 brings a systems biology approach, “systems vaccinology”, to investigate immune response programing by IL-15 and RhCMV/SIV vaccine. Our goal is to define the molecular response by which IL-15 and RhCMV/SIV vaccine program the protection-predictive immune phenotype in whole blood to vaccination, what we term as the “whole blood protection-predictive transcriptomic signature” [wbPPTS] that predicts and underlies vaccine protection from SIV infection. We will conduct three Aims including i) Determine the response to IL-15 in monocytes and T cells; ii) Define the tissue and cell-specific transcriptome correlates of IL-15 signaling linked with RhCMV/SIV vaccination phenotype to program the wbPPTS, and iii) Validate RhCMV/SIV vaccination tissue and wbPPTS signature linkage with protection against SIV challenge. Our research design features in vitro and ex vivo models for analyses of cell signaling/responses to IL-15, and in vivo analyses of cell and tissue application of three "omics" platforms including single cell RNA sequencing (scRNAseq and CITEseq), bulk RNAseq, and tissue spatial profiling. Our bioinformatics/computational analyses will integrate functional genomics data sets with immune response and protection phenotypes to determine the molecular and cellular features directing the wbPPTS and vaccine protection. We will conduct bioinformatics of RhCMV/SIV transcriptomic responses in an independent vaccination/SIV challenge cohort to ascertain specific tissue signature of protection and the wbPPTS. This work will be conducted in a collaborative framework conjunction with Cores A-C and Project 1.

项目2带来了系统生物学的方法，“系统疫苗学”，研究免疫反应 用IL-15和RhCMV/SIV疫苗编程。我们的目标是确定IL-15和 RhCMV/SIV疫苗程序的保护预测免疫表型在全血接种，什么 我们称之为“全血保护-预测转录组签名”[wbPPTS]，它预测并支持 预防SIV感染的疫苗。我们将进行三个目标，包括i）确定对IL-15的反应 ii）定义IL-15信号传导相关的组织和细胞特异性转录组相关物; 使用RhCMV/SIV疫苗接种表型对wbPPTS进行编程，以及iii）验证RhCMV/SIV疫苗接种组织 以及具有针对SIV挑战的保护的wbPPTS签名链接。我们的研究设计特点是在体外， 用于分析细胞信号传导/对IL-15的应答的离体模型，以及细胞和组织应用的体内分析 三个“组学”平台，包括单细胞RNA测序（scRNAseq和CITEseq），批量RNAseq， 组织空间分布我们的生物信息学/计算分析将整合功能基因组学数据集 与免疫应答和保护表型，以确定分子和细胞特征，指导 wbPPTS和疫苗保护。我们将进行RhCMV/SIV转录组反应的生物信息学研究， 独立的疫苗接种/SIV攻毒队列，以确定特定的保护组织特征， wbPPTS。这项工作将在与核心A-C和项目1合作的框架内进行。