Project 2

项目2

• 批准号: 10599216
• 负责人: Maria Virginia Pascual
• 金额: $ 69.95万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599216
• 关键词: 2019-nCoV; ATAC-seq; Adult; Affect; Antibody Response; Antibody titer measurement; B-Lymphocytes; Bacterial Infections; Biological Assay; Blood; Blood Cells; CD8-Positive T-Lymphocytes; COVID-19 vaccine; Cell Count; Cell Nucleus; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Child; Childhood; Chromatin; Custom; Data; Data Set; Development; Disease; Enrollment; Epigenetic Process; Exposure to; Gene Expression Profile; Genetic Transcription; Health; Human; Immune; Immune response; Immune system; Immunity; Immunologic Monitoring; Immunophenotyping; Infant; Infection; Influenza; Influenza vaccination; Knowledge; Learning; Life; Longevity; Longitudinal Studies; Molecular; Monitor; Outcome; Participant; Pathway interactions; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Phenotype; Population; Production; Property; Risk; SARS-CoV-2 infection; Sample Size; Sampling; Shapes; Systems Biology; Technology; Vaccination; Vaccines; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; age group; age related; analysis pipeline; commensal microbes; cytokine; epigenome; experience; flexibility; genome-wide; high risk; human old age (65+); immune function; imprint; influenza infection; innovative technologies; multidimensional data; pathogenic microbe; postnatal; respiratory virus; response; seasonal influenza; severe COVID-19; tool; transcriptome; transcriptome sequencing; trend

ABSTRACT Infants and young children are at higher risk for severe manifestations of certain respiratory viruses, such as influenza and RSV, compared to older children or adults. Interestingly, SARS-CoV-2 infection has shown the opposite trend, with infants being at lower risk of serious outcomes. The molecular and cellular mechanisms underpinning vulnerability to some infections and protection from others are poorly understood, but intrinsic properties of the post-natal immune system might be at their core. Systems biology tools can resolve these knowledge gaps through detailed analysis of the transcriptome, epigenome and function of immune cell populations across the life span. This project capitalizes on our experience in studying the human immune system through childhood in health and disease, and the availability of immune monitoring assays for use with small-volume samples. Recently, we have leveraged innovative technologies, i.e., ATAC-seq for assessing chromatin accessibility, RNA-seq, high-definition cellular immunophenotyping at the bulk and single cell levels as well as custom-built integrative analysis pipelines. Our preliminary data confirm that we can maximally leverage infant samples to capture transcriptional and regulatory genome-wide signatures associated with the developing immune system in response to viral infections and vaccination with unprecedented granularity. We propose to assess the immune responses to infection with two viruses, influenza and SARS-CoV-2, occurring in the first six months of life by leveraging our immune profiling platform. We will track age-related changes in immune cell composition, transcriptome and epigenome during this first encounter with the virus and will subsequently monitor these parameters upon vaccination against these viruses yearly for a period of three years. Aim 1 will define the phenotype/cell composition, transcriptome and epigenome of infant PBMCs upon their first encounter with either Influenza or SARS-CoV-2 viruses. Aim 2 will Characterize the PBMC phenotype/cell composition, transcriptome and epigenome in response to vaccination against influenza and SARS-CoV-2.

抽象的 婴儿和幼儿患某些呼吸道病毒的严重表现的风险较高，例如 与年龄较大的儿童或成人相比，流感和RSV。有趣的是，SARS-COV-2感染显示了 相反的趋势，婴儿的严重预后风险较低。分子和细胞机制 对某些感染和对其他感染的保护的脆弱性的理解很少，但内在 产后免疫系统的特性可能是其核心。系统生物学工具可以解决这些 通过详细分析转录组，表观基因组和免疫细胞功能的知识差距 整个寿命的种群。该项目利用我们研究人类免疫的经验 通过儿童期在健康和疾病中的系统，以及用于使用的免疫监测测定法 小体积样品。最近，我们利用了创新技术，即ATAC-SEQ评估 染色质可及性，RNA-seq，高清细胞免疫表型在整体和单细胞水平 以及定制的集成分析管道。我们的初步数据证实我们可以最大程度地 利用婴儿样本来捕获与 响应病毒感染和疫苗接种，以前所未有的粒度发展免疫系统。 我们建议评估两种病毒感染的免疫反应，即流感和SARS-COV-2， 通过利用我们的免疫分析平台，发生在生命的头六个月中。我们将跟踪与年龄有关的 在第一次与病毒相遇期间，免疫细胞组成，转录组和表观基因组的变化 并随后在针对这些病毒接种后每年监测这些参数， 三年。 AIM 1将定义婴儿PBMC的表型/细胞组成，转录组和表观基因组 首次与流感或SARS-COV-2病毒相遇。 AIM 2将表征PBMC 表型/细胞组成，转录组和表观基因组对疫苗接种，对流感和疫苗接种 SARS-CoV-2。