High Precision System Analysis of Infant Immune Responses

婴儿免疫反应的高精度系统分析

• 批准号: 9751197
• 负责人: Jacques F Banchereau
• 金额: $ 52.29万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751197
• 关键词: ATAC-seq; Adult; Affect; Age-Months; Antibody Response; Antigens; Bacterial Infections; Biological Assay; Blood; Blood Volume; Blood specimen; Cause of Death; Cells; Characteristics; Child; Chromatin; Clinical; Code; Communicable Diseases; Competence; Complex; Custom; Cytometry; Data; Data Set; Development; Disease; Dose; Flow Cytometry; Foundations; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Genomics; Goals; Human; Hybrids; Immune; Immune response; Immune system; Immunity; Immunization Programs; Immunogenomics; Immunophenotyping; Infant; Infant Health; Infection; Intervention; Knowledge; Life; Maps; Molecular; Molecular Profiling; Morbidity - disease rate; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Population; Protein Isoforms; Regulation; Resolution; Sample Size; Sampling; Shapes; Systems Analysis; Systems Biology; Technology; Time; Transcript; Untranslated RNA; Vaccination; Vaccines; Work; age related; analysis pipeline; analytical tool; base; bioinformatics tool; cell type; cohort; design; epigenome; epigenomics; experience; flexibility; genomic signature; high risk; immune function; imprint; innovation; innovative technologies; insight; longitudinal analysis; mortality; neutralizing antibody; response; single molecule real time sequencing; tool; transcriptome; transcriptome sequencing; transcriptomics; ATAC-seq; Adult; Affect; Age-Months; Antibody Response; Antigens; Bacterial Infections; Biological Assay; Blood; Blood Volume; Blood specimen; Cause of Death; Cells; Characteristics; Child; Chromatin; Clinical; Code; Communicable Diseases; Competence; Complex; Custom; Cytometry; Data; Data Set; Development; Disease; Dose; Flow Cytometry; Foundations; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Genomics; Goals; Human; Hybrids; Immune; Immune response; Immune system; Immunity; Immunization Programs; Immunogenomics; Immunophenotyping; Infant; Infant Health; Infection; Intervention; Knowledge; Life; Maps; Molecular; Molecular Profiling; Morbidity - disease rate; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Population; Protein Isoforms; Regulation; Resolution; Sample Size; Sampling; Shapes; Systems Analysis; Systems Biology; Technology; Time; Transcript; Untranslated RNA; Vaccination; Vaccines; Work; age related; analysis pipeline; analytical tool; base; bioinformatics tool; cell type; cohort; design; epigenome; epigenomics; experience; flexibility; genomic signature; high risk; immune function; imprint; innovation; innovative technologies; insight; longitudinal analysis; mortality; neutralizing antibody; response; single molecule real time sequencing; tool; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY This project seeks to surmount current limitations in our understanding of early infant immunity through longitudinal genomic and cellular studies of immune development and primary responses to routine two-month vaccines. Infants and young children are more susceptible to invasive infections than adults owing to overall reduced competency of protective immune responses, including to vaccines, which require administration of multiple doses over several months for adequate long-term protection. While immunization programs have dramatically decreased the global morbidity and mortality caused by infections, it remains that infectious diseases are the most frequent cause of death in infants and young children. The cellular, molecular and genomic mechanisms that contribute to this vulnerability are largely unknown. Ever more powerful tools in genomics and systems biology offer exciting opportunities to resolve these knowledge gaps through detailed analysis of the transcriptomic, epigenomic and functional signatures of infant immune cell populations. However, such studies have been limited by the difficulty in accessing clinical samples from infants, the incompatibility of many genomic technologies for use in small-volume samples, and the lack of bioinformatic tools for integrating and interpreting complimentary yet complex datasets. This proposal will capitalize on our experience studying the infant immune response, our access to infant populations, and our expertise in developing immunogenomic assays for use in human blood-derived immune cells (PBMCs). Specifically, we propose a longitudinal analysis of PBMCs from infants i) at 2, 6 and 12 months, to establish the baseline cellular, phenotypic and genomic signatures of immune development (Aim 1), and ii) at key time points over the course of routine two-month vaccinations, to identify the cellular, phenotypic and genomic signatures associated with primary immune responses to vaccines (Aim 2). We will use an innovative immunogenomic Profiling and Analysis Pipeline (iPAP) we developed that allows us to extract maximal transcriptomic (RNA-seq), epigenomic (ATAC-seq), isoformic (SMRT-seq), cytometric (50-parameter flow cytometry) and immunophenotypic (CyTOF) information from a single infant blood sample, and to integrate these distinct datasets for unparalleled depth of insight into the correlated cellular and genomic signatures of immune development and vaccine responsiveness. Our approach is unbiased, multifaceted and highly technology-driven, combining many of the most cutting-edge genomic and quantitative cell-based technologies with our deep experience in applying these technologies for use in human infant immune cells. In line with the goals of this RFA, this project will yield a comprehensive dataset from infants that can be used to identify fundamental mechanisms and pathways associated with immune development and primary responses to vaccines, and will set the stage for future studies aimed at designing new interventions that induce more potent and protective immune responses for young infants.

项目摘要 该项目试图在我们对早期婴儿免疫力的理解中克服当前的限制 通过纵向基因组和细胞研究免疫发育以及对 常规的两个月疫苗。婴儿和幼儿比侵入性感染更容易 由于总体上降低了保护性免疫反应的能力，包括疫苗，包括疫苗，成年人 需要在几个月内服用多剂剂量以进行足够的长期保护。尽管 免疫计划大大降低了感染引起的全球发病率和死亡率， 仍然是传染病是婴儿和幼儿中最常见的死亡原因。这 导致这种脆弱性的细胞，分子和基因组机制在很大程度上未知。曾经 基因组学和系统生物学中更强大的工具为解决这些知识提供了令人兴奋的机会 通过详细分析婴儿免疫的转录组，表观基因组和功能特征的差距 细胞种群。但是，此类研究受到了难以获取临床样本的困难 婴儿，许多基因组技术用于小体积样本的不相容性，缺乏 用于集成和解释免费但复杂数据集的生物信息学工具。该提议将 利用我们研究婴儿免疫反应，我们获得婴儿人群的经验以及我们的经验 用于开发用于人类血液衍生免疫细胞（PBMC）的免疫基因组学测定方面的专业知识。 具体而言，我们建议对婴儿的PBMC进行纵向分析i）2、6和12个月，以建立 免疫发育的基线细胞，表型和基因组特征（AIM 1）和II）在关键时间 在常规两个月疫苗的过程中，要确定细胞，表型和基因组的疫苗接种 与一级免疫反应相关的签名（AIM 2）。我们将使用创新 我们开发的免疫基因组分析和分析管道（IPAP），使我们能够提取最大 转录组（RNA-SEQ），表观基因组（ATAC-SEQ），同基（SMRT-SEQ），细胞仪（50参数流量流量） 细胞仪）和来自单个婴儿血液样本的免疫表型（Cytof）信息，并整合 这些独特的数据集，以无与伦比的深度深入了解相关的细胞和基因组特征 免疫发育和疫苗反应。我们的方法是公正的，多方面的，高度 技术驱动的，结合了许多最前沿的基因组和基于定量的细胞技术 凭借我们在应用这些技术中用于人类婴儿免疫细胞中的深刻经验。与 该RFA的目标，该项目将产生婴儿的全面数据集 确定与免疫发育和原发性相关的基本机制和途径 对疫苗的反应，并将为未来研究旨在设计新干预措施奠定基础 这会引起对年轻婴儿的更有效和保护性免疫反应。