Immune Development Across the Life Course: Integrating Exposures and Multi-Omics in the Boston Birth Cohort

整个生命过程中的免疫发展：在波士顿出生队列中整合暴露和多组学

基本信息

批准号：
10418079
负责人：
Hongkai Ji
金额：
$ 82.22万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10418079
关键词：
18 year old Address Adolescence Affect Age Air Pollution Allergens Allergic Allergic Disease Antibodies Antibody Repertoire Antibody Response Asthma Attention Bacterial Proteins Birth Black race Blood Boston Cadmium Child Child Development Childhood Childhood Asthma Clinical Clinical Data Cohort Studies DNA Methylation Data Data Element Development Discipline Disease Dose Enrollment Environmental Exposure Environmental Pollutants Exposure to Food Hypersensitivity Funding Future Genetic Genome Genus staphylococcus Goals Growth Health High Prevalence IgE Immune Immune response Immune system Immunity Immunoglobulin G Individual Intervention Knowledge Laboratories Lead Life Life Cycle Stages Link Literature Low income Measures Mercury Microbe Molecular Mothers Newborn Infant Outcome Pathway interactions Peer Review Perinatal Phage ImmunoPrecipitation Sequencing Phenotype Poly-fluoroalkyl substances Prevention Prognosis Proteins Publications Recurrence Regulation Reporting Research Resources Risk Risk Factors Signal Transduction Statistical Methods Techniques Technology Umbilical Cord Blood United States National Institutes of Health Venous Virus Wheezing age group analytical method biobank biological specimen archives cohort commensal microbes computer infrastructure early childhood early life exposure effective intervention environmental allergen epidemiologic data epigenome follow-up food allergen high risk high risk population human virome improved in utero metabolome metabolomics multiple omics novel marker novel strategies pathogenic microbe pollutant postnatal prenatal prenatal exposure prospective protective factors response software development statistics therapeutic target toxic metal toxicant

项目摘要

Abstract Our overarching goal is to investigate the impact of early life immune response to a broad array of pathogenic and commensal microbes and exposure to multiple environmental pollutants on the development and prognosis of allergic diseases from birth up to age 18 years and their underlying molecular pathways. Our project is motivated by growing evidence that in-utero and the first few years of life are critical windows for the development of immunity, and by observations that early life exposures to microbes and environmental pollutants may have a profound impact on future risk of allergic diseases. To achieve our goal, we will leverage the rich resources of the Boston Birth Cohort (BBC), with ~3,500 mother-child pairs who were enrolled at birth and followed prospectively. Through our prior research in the BBC, we have established essential clinical, laboratory and computational infrastructures, and obtained longitudinal epidemiological and clinical data, and multi-omics (genome, epigenome, metabolome) data as well as archived biospecimens. We have shown that the BBC is a high-risk population for adverse environmental exposures and the children of the BBC have a high prevalence of immune-related disorders, including food allergies, early childhood recurrent wheezing and childhood asthma. The breadth, depth, and high quality of the BBC data and biorepository have been demonstrated in over 120 peer-reviewed publications. We also have generated compelling preliminary data to support our study aims and hypotheses. Specifically, by including 1,000 mother-child dyads of the BBC with key longitudinal data elements and biospecimens from birth up to age 18 years, we aim to investigate: (1) effects of early life immune response to microbes on child allergic phenotypes; (2) effects of early life exposure to environmental pollutants (e.g., air pollution, toxic metals) on child allergic phenotypes; and (3) molecular pathways underlying the link between early life environmental exposures and allergic diseases. We will harness cutting-edge antibody profiling technology (PhIP-Seq) to profile IgG and IgE antibodies in 1,000 BBC children at three important developmental windows (birth, 1-2 years, and 15-18 years). This will provide deep phenotyping of a child’s antibody profile and identify longitudinal changes in the context of prenatal, perinatal, and postnatal genetic and environmental interactions. Our ability to profile the antibody repertoire and define allergic phenotypes across critical developmental windows allow us to delineate their longitudinal trajectories, temporal and dose-response relationships between the exposures and outcomes. Successful completion of this study will help identify important early life risk and protective factors, along with novel biomarkers for prediction or therapeutic targets. Ultimately, we hope that high-risk newborns can be identified, and effective interventions can be initiated during the earliest developmental windows when they may have the greatest life- long benefit.

抽象的我们的总体目标是调查早期免疫反应对一系列广泛阵列的影响致病性和共生微生物以及对发育中多种环境污染物的暴露从出生到18岁的过敏性疾病及其潜在的分子途径的预后。我们的越来越多的证据表明，In-Utero和生命的头几年是关键的窗口的动机。免疫的发展，以及通过早期生命暴露于微生物和环境的观察污染物可能会对未来的过敏性疾病风险产生深远的影响。为了实现我们的目标，我们将利用波士顿出生队列（BBC）的丰富资源，约有3500对母子对并前瞻性地跟随。通过先前在BBC的研究，我们建立了基本的临床，实验室和计算基础设施，并获得了纵向流行病学和临床数据，以及多词（基因组，表观基因组，代谢组）数据以及存档的生物测量。我们已经表明英国广播公司是不利环境暴露的高风险人口，英国广播公司的孩子有免疫相关疾病的高患病率包括食物过敏，幼儿复发和童年哮喘。 BBC数据和生物座的宽度，深度和高质量已经在120多个经过同行评审的出版物中证明。我们还生成了引人入胜的初步数据支持我们的研究目标和假设。具体而言，通过包括1,000个BBC的母子二元关键的纵向数据元素和从出生到18岁的生物测量，我们的目标是研究：（1）早期生命对微生物的免疫反应对儿童过敏表型的影响；（2）早期曝光的影响致儿童过敏表型的环境污染物（例如空气污染，有毒金属）；（3）分子早期生活环境暴露与过敏性疾病之间联系的途径。我们将线束前沿抗体分析技术（PHIP-SEQ）介绍了1,000 BBC中的IgG和IgE抗体在三个重要的发展窗户（出生，1-2岁和15-18岁）处的儿童。这将提供深度儿童抗体谱的表型，并在产前，围产期，以及产后遗传和环境相互作用。我们介绍抗体库和定义的能力关键发育窗口中的过敏表型使我们能够描述其纵向轨迹，暴露与结果之间的临时和剂量反应关系。成功完成这项研究将有助于确定重要的早期生命风险和受保护的因素，以及新颖的生物标志物预测或治疗靶标。最终，我们希望可以确定高风险的新生儿，有效干预措施可以在最早的发育窗口中开始，当时它们可能拥有最大的生活 - 长期的好处。