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

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.

项目概要 该项目旨在克服目前我们对早期婴儿免疫理解的局限性 通过免疫发育和初级反应的纵向基因组和细胞研究 常规两个月疫苗。婴幼儿比儿童更容易受到侵袭性感染 成年人由于保护性免疫反应（包括疫苗）的能力总体下降， 需要在几个月内给予多次剂量以获得充分的长期保护。尽管 免疫规划大大降低了全球感染引起的发病率和死亡率， 传染病仍然是婴幼儿最常见的死亡原因。这 造成这种脆弱性的细胞、分子和基因组机制在很大程度上是未知的。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来找出差距 细胞群。然而，此类研究因难以获取临床样本而受到限制。 婴儿、许多基因组技术在小体积样本中使用的不兼容性以及缺乏 用于集成和解释互补但复杂的数据集的生物信息工具。该提案将 利用我们研究婴儿免疫反应的经验、我们接触婴儿群体的机会以及我们的研究成果 开发用于人血源性免疫细胞 (PBMC) 的免疫基因组检测的专业知识。 具体来说，我们建议对婴儿 i) 在 2、6 和 12 个月时的 PBMC 进行纵向分析，以确定 关键时间免疫发育的基线细胞、表型和基因组特征（目标 1）和 ii） 在为期两个月的常规疫苗接种过程中进行积分，以确定细胞、表型和基因组 与疫苗初次免疫反应相关的特征（目标 2）。我们将使用创新的 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)、同工型 (SMRT-seq)、细胞计数（50 参数流式细胞仪） 来自单个婴儿血液样本的细胞计数）和免疫表型（CyTOF）信息，并整合 这些不同的数据集可以对相关细胞和基因组特征进行无与伦比的深入洞察 免疫发育和疫苗反应。我们的方法是公正的、多方面的和高度 技术驱动，结合了许多最前沿的基因组和定量细胞技术 凭借我们在将这些技术应用于人类婴儿免疫细胞方面的丰富经验。符合 为了实现 RFA 的目标，该项目将产生婴儿的综合数据集，可用于 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，并将为旨在设计新干预措施的未来研究奠定基础 为小婴儿诱导更有效和保护性的免疫反应。