Maternal SARS-CoV-2 infection, placenta biology, and neurodevelopmental outcomes in the offspring

母体 SARS-CoV-2 感染、胎盘生物学和后代的神经发育结果

• 批准号: 10819677
• 负责人: Gianluca Ursini
• 金额: $ 72.14万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10819677
• 关键词: 2019-nCoV; Address; Affect; Biological Markers; Biology; Brain; Caring; Child; Data; Development; Disease; Disease Outbreaks; Ethnic Origin; Event; Fostering; Future; Genes; Genomics; Goals; Guidelines; Infant; Infection; Inflammatory; Intervention; Knowledge; Mediating; Mental Health; Mission; Molecular Biology; Mothers; Neurodevelopmental Disorder; Newborn Infant; Outcome; Placenta; Placental Biology; Pregnancy; Pregnancy Complications; Prevention; Process; Psychometrics; Public Health; Readiness; Recovery; Research; Risk; Risk Factors; SARS-CoV-2 exposure; SARS-CoV-2 infection; Sampling; Stress; Testing; Time; Tissues; United States National Institutes of Health; Vaccinated; Vulnerable Populations; Woman; Work; antenatal; biomarker identification; current pandemic; fetal; fetal blood; genomic predictors; immune activation; improved; innovation; male; neurodevelopment; offspring; pandemic disease; perinatal outcomes; placental morphology; postnatal; potential biomarker; prenatal exposure; protein expression; sex; social health determinants; unvaccinated

PROJECT SUMMARY The extent to which SARS-CoV-2 infection in pregnancy affects the biology of the maternal-placental-fetal triad and neurodevelopmental trajectory in offspring is not known. Early studies indicate that SARS-CoV-2 can induce alterations in the placenta which can increase risk for adverse perinatal outcomes and, based on knowledge from other infectious and inflammatory disorders in pregnancy and preliminary data on the current pandemic, increase risk for neurodevelopmental disorders (NDDs) in offspring. The long-term goal of this proposal is to timely identify the impact of the ongoing pandemic on the neurodevelopment (ND) of infants born following maternal SARS-CoV-2 infection. The objective is to analyze the relationships between maternal SARS-CoV-2 infection, placenta biology, and ND outcomes, in interaction with genomic risk (GRSs) for NDDs and sex. The central hypothesis is that maternal SARS-CoV-2 infection and infection-related pregnancy complications affect early paths of brain development, particularly in those with high GRSs for NDDs and in males, and that these effects are mediated by alterations in placenta morphology and molecular biology. The rationale underlying the proposal is that completion will define critical targets for identification and potentially prevention of NDDs in the offspring of infected mothers. The central hypothesis will be tested by pursuing the following specific aims: 1) Determine pregnancy, placental, and newborn outcomes following antenatal SARS-CoV-2 infection; 2) Investigate the relationship between SARS-CoV-2 maternal infection, GRSs for NDDs, and placenta molecular biology; 3) Evaluate the relationship between maternal SARS-CoV-2 infection in pregnancy, offspring genomic risk factors for NDDs, and ND outcomes. We will pursue the aims using an innovative combination of placenta tissue and maternal and fetal blood analysis, and comprehensive psychometric testing of early child ND. We will compare unvaccinated and vaccinated woman-placenta-infant triads exposed to SARS-CoV-2 infection during pregnancy to unvaccinated and vaccinated controls. We will study how, in a large sample of multiple ethnicities, maternal infection and stress, social determinants of health, GRSs for NDDs, and sex, adversely affect neurodevelopmental outcomes of the offspring though processes mediated by alteration in placenta gene/protein expression and maternal immune activation. The proposed research is significant, because it will characterize the relationship between maternal SARS-CoV-2 infection and neurodevelopmental outcome of the offspring, and also identify factors, molecules and genomic predictors that modulate, mediate or – as biomarkers – reveal such relationship. The proximate expected outcome of this work will be an understanding of the mechanisms through which maternal infection, genomic risk and sex, placenta biology, and postnatal factors may contribute to define risk for NDDs. The results will have an immediate positive impact to inform targeted interventions and guidelines for SARS-CoV-2 exposed women and their infants, impacting how clinicians evaluate and care for these cases, and to identify potential biomarkers of risk for NDDs in offspring of mothers with infection during pregnancy.

项目摘要 SARS-COV-2感染在怀孕中的多大程度影响孕产妇 - 遗传三合会的生物学 后代中的神经发育轨迹尚不清楚。早期研究表明SARS-COV-2可以诱导 放act的改变，可以增加不良围产期结局的风险，并基于知识 来自怀孕的其他感染和炎症性疾病，以及有关当前大流行的初步数据， 增加后代神经发育障碍（NDD）的风险。该提议的长期目标是 及时确定正在进行的大流行对出生婴儿神经发育（ND）的影响 母体SARS-COV-2感染。目的是分析母体SARS-COV-2之间的关系 与基因组风险（GRS）相互作用，感染，胎盘生物学和ND结局。这 中心假设是母体SARS-COV-2感染和与感染有关的妊娠并发症会影响 大脑发育的早期途径，特别是在NDD和男性高的人中 效果是由Pliceta形态和分子生物学的改变介导的。基础的基本原理 提案是，完成将定义识别和潜在预防NDD的关键目标 感染母亲的后代。中心假设将通过追求以下特定目的来检验：1） 确定静脉SARS-COV-2感染后的怀孕，斑点和新生儿结局； 2） 研究SARS-COV-2 MATER感染，NDDS的GRS和Plopeta Molecular之间的关系 生物学; 3）评估怀孕中母体SARS-COV-2感染的关系，后代基因组 NDD的危险因素和ND结果。我们将使用Plopeta的创新组合来追求目标 组织，母体和胎儿血液分析，以及早期儿童的全面心理测试。我们将 比较未接种疫苗和接种疫苗的女性 - 替代女性侵袭性三合会，暴露于SARS-COV-2感染期间 怀孕至未接种和接种疫苗的控制。我们将研究在大量多种种族样本中如何 孕产妇感染和压力，健康的社会决定因素，NDD的GRS以及性别，不利影响 后代的神经发育结果，尽管由pleceta基因/蛋白质改变介导的过程 表达和母体免疫激活。拟议的研究很重要，因为它将表征 母体SARS-COV-2感染与后代的神经发育结果与 还确定调节，介导或（作为生物标志物）的因素，分子和基因组预测因子揭示了这种情况 关系。这项工作的直接预期结果将是对通过机制的理解 哪些母体感染，基因组风险和性别，lopeta生物学和产后因素可能有助于定义 NDD的风险。结果将对有针对性的干预措施和准则产生直接的积极影响 对于SARS-COV-2暴露的妇女及其婴儿，影响临床医生如何评估和照顾这些情况， 并确定怀孕期间感染母亲后代的NDD风险的潜在生物标志物。