Maternal inflammation in relation to offspring epigenetic aging and neurodevelopment

与后代表观遗传衰老和神经发育相关的母体炎症

• 批准号: 10637981
• 负责人: Stephanie Shiau
• 金额: $ 71.76万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637981
• 关键词: 4 year old; Acceleration; Adult; Adverse effects; Affect; Age; Aging; Animals; Anxiety; Biological Aging; Biological Markers; Biological Specimen Banks; Biometry; Birth; Blood; Body mass index; C-reactive protein; Child; Childhood; Chronology; Clinical; Cognitive; Cognitive Science; Collection; DNA Methylation; Data; Development; Elderly; Environment; Epigenetic Process; Exposure to; Fetus; First Pregnancy Trimester; Future; Gestational Age; Goals; Health; IL8 gene; Immunology; Impaired cognition; Infant; Infant Development; Inflammation; Inflammatory; Infrastructure; Intelligence; Interdisciplinary Study; Interferon Type II; Interleukin-1 beta; Interleukin-2; Interleukin-6; Intervention; Knowledge; Link; Longevity; Longitudinal Studies; Maternal Age; Maternal and Child Health; Measures; Mediating; Methylation; Molecular; Morbidity - disease rate; Neurocognition; Neurocognitive; Neurodevelopmental Disorder; Obesity; Outcome; Perinatal Epidemiology; Phenotype; Poverty; Pregnancy; Pregnancy Trimesters; Pregnant Women; Process; Reporting; Research; Risk; Signal Transduction; Specimen; Stress; Swab; TNF gene; Testing; Translating; Trauma; United States National Institutes of Health; Visit; Wechsler Scales; Work; adverse outcome; bead chip; biobank; clinical epidemiology; clinically relevant; cohort; cost effective; cost efficient; critical developmental period; cytokine; early childhood; epidemiology study; epigenomics; executive function; fetal; genomic biomarker; human old age (65+); improved; in utero; infancy; innovation; insight; life history; neurodevelopment; novel; offspring; prenatal; prenatal exposure; prepregnancy; psychologic; sex; sociodemographics; systemic inflammatory response; young adult

PROJECT SUMMARY Maternal inflammation during pregnancy, as defined by elevated levels of circulating pro-inflammatory cytokines, can have adverse effects on offspring neurodevelopment. However, mechanisms remain elusive. Accelerated biological aging has been proposed as an underlying mechanism by which prenatal exposures influence future health. This process can be evaluated through epigenetic clocks, which estimate epigenetic age based on DNA methylation levels, and are widely used as clinically relevant biomarkers that measure epigenetic age acceleration. To date, pediatric epigenetic studies have been limited by: (1) use of adult-specific or all-age clocks; and (2) scant longitudinal epigenetic data due to challenges of pediatric blood collection. Here, we use a newly developed pediatric-specific clock [the pediatric buccal epigenetic (PedBE) clock] that can be evaluated using non-invasive buccal swabs, facilitating repeat measures across childhood. Our long-term goal is to identify easy- to-measure biomarkers in infants and young children that reflect exposure to maternal inflammation during pregnancy and predict subsequent risk for morbidity in offspring. This innovative and cost-effective longitudinal study will leverage the infrastructure, biorepository, and extant data of a rigorously phenotyped cohort of healthy pregnant women and their offspring followed from the first trimester through age 4 (R01HD083369, UH3OD023349). The Understanding Pregnancy Signals and Infant Development (UPSIDE-ECHO) cohort includes comprehensive assessments of inflammation across pregnancy, repeated measures of neurodevelopment across childhood, detailed psychological, sociodemographic, clinical, and life history data, and a rich repository of biospecimens collected from 2015 – 2024 (age 3-4 visits in progress). Our central hypothesis is that maternal inflammation during pregnancy accelerates the offspring’s epigenetic age, adversely influencing neurodevelopment. Our interdisciplinary research team is comprised of experts in maternal and child health, epigenomics, immunology, cognitive science, perinatal epidemiology, and biostatistics. In Aim 1, we will establish trajectories of longitudinal changes in offspring epigenetic age from birth through 4 years of age and identify factors associated with offspring epigenetic age acceleration. In Aim 2, we will study associations between maternal inflammation during pregnancy and offspring epigenetic age acceleration. In Aim 3, we will examine associations between offspring epigenetic age and neurocognition through age 4, and explore if epigenetic age mediates the association between maternal inflammation during pregnancy and neurocognitive outcomes. The research proposed in this R01 is significant because it will generate new insights into the link between maternal inflammation during pregnancy and genomic biomarkers of accelerated aging, with a focus on how accelerated epigenetic age can impact offspring neurocognition. This formative work will advance our understanding of how epigenetic age trajectories change across a critical developmental period and identify opportunities for maternal/offspring interventions to improve neurocognitive outcomes across the entire lifespan.

项目总结