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：
10704536
负责人：
Hongkai Ji
金额：
$ 79.22万
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/10704536
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 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 Staphylococcus aureus 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 predictive marker prenatal prenatal exposure prospective protective factors response software development statistics therapeutic target toxic metal toxicant transmission process

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.

抽象的我们的首要目标是研究生命早期免疫反应对多种疾病的影响病原微生物和共生微生物以及接触多种环境污染物对发展的影响从出生到 18 岁的过敏性疾病的预后及其潜在的分子途径。该项目的动机是越来越多的证据表明，子宫内和生命的最初几年是婴儿出生的关键时期。免疫力的发展，以及通过观察生命早期接触微生物和环境污染物可能对未来过敏性疾病的风险产生深远的影响。为了实现我们的目标，我们将利用杠杆作用。波士顿出生队列 (BBC) 的丰富资源，约有 3,500 对出生时登记的母子通过我们之前在 BBC 的研究，我们已经建立了必要的临床、实验室和计算基础设施，并获得纵向流行病学和临床数据，以及我们已经证明了多组学（基因组、表观基因组、代谢组）数据以及存档的生物样本。 BBC 是不良环境暴露的高危人群，BBC 的孩子有免疫相关疾病的高患病率，包括食物过敏、儿童早期反复喘息和 BBC 数据和生物数据库的广度、深度和高质量得到了广泛认可。我们还生成了令人信服的初步数据来证明这一点。具体来说，通过纳入 BBC 的 1,000 名母子二人组来支持我们的研究目标和假设。从出生到 18 岁的关键纵向数据元素和生物样本，我们的目标是调查：(1) 生命早期对微生物的免疫反应对儿童过敏表型的影响；（2）生命早期接触的影响；环境污染物（例如空气污染、有毒金属）对儿童过敏表型的影响；以及（3）分子过敏；我们将研究早期环境暴露与过敏性疾病之间的联系。利用尖端抗体分析技术 (PhIP-Seq) 分析 1,000 个 BBC 中的 IgG 和 IgE 抗体这将为处于三个重要发展窗口（出生、1-2 岁和 15-18 岁）的儿童提供深入的帮助。对儿童抗体谱进行表型分析，并识别产前、围产期、以及出生后遗传和环境相互作用的能力。跨关键发育窗口的过敏表型使我们能够描绘它们的纵向轨迹，暴露和结果之间的时间和剂量反应关系。这项研究将有助于确定重要的早期生命风险和保护因素，以及新的生物标志物最终，我们希望能够识别出高危新生儿并有效。干预措施可以在最早的发育窗口期开始，此时他们可能有最长的寿命。长益。