The Clock is Ticking: Epigenetic Age Acceleration as a Biomarker of Uterine Function in Pregnancy

时钟在滴答作响：表观遗传年龄加速作为妊娠期子宫功能的生物标志物

• 批准号: 10268221
• 负责人: Elise N Erickson
• 金额: $ 9.41万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-24 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10268221
• 关键词: Acceleration; Age; Age-Years; Aging; American; Biological; Biological Aging; Biological Markers; Biological Specimen Banks; Birth; Blood; Blood specimen; Cesarean section; Childbirth; Chronology; Clinical Data; Complex; DNA; DNA Methylation; Data; Data Set; Economics; Elderly; Enrollment; Environment; Environmental Exposure; Epigenetic Process; Fetal Tissues; Functional disorder; Gene Expression; Gestational Age; Goals; Health; High Risk Woman; Impairment; Individual; Induced Labor; Infant; Knowledge; Light; Link; Longevity; Maternal Health; Maternal Mortality; Measures; Mediator of activation protein; Messenger RNA; Methods; Modeling; Modification; Morbidity - disease rate; Mothers; Myometrial; National Institute of Child Health and Human Development; Newborn Infant; Outcome; Patient Self-Report; Perinatal Care; Personal Satisfaction; Persons; Phenotype; Postpartum Hemorrhage; Pregnancy; Pregnancy Outcome; Prolonged labor; Proteins; Psychometrics; Psychosocial Stress; Research; Research Methodology; Role; Sampling; Site; Social Environment; Source; Stress; Testing; Tissue Banks; Tissues; Training; Umbilical Cord Blood; United States; Uterus; Woman; Work; adverse outcome; age group; age related; base; career development; chemical group; data repository; epigenetic marker; experience; fetal; genome wide association study; genome-wide; genomic data; health disparity; high risk; improved; in utero; indexing; innovation; mRNA Expression; maternal morbidity; maternal outcome; methylation pattern; mortality; myometrium; novel marker; older women; perinatal morbidity; predictive marker; psychosocial; repository; sex; social; socioeconomics; stressor; tool; uterine contractility; young woman

Women of advanced age (> 35 years of age) are at significantly higher risk for adverse outcomes during childbirth, compared to younger women. This problem is both critical and growing, as the number of births occurring in this age group have increased nine-fold over the last 40 years, escalating maternal morbidity and mortality in the US. Given that prolonged labor, Cesarean birth and postpartum hemorrhage are more common among older women, a decline in uterine function (contractility) with advancing age may be a source of labor- related dysfunction. Prior studies have shown that individuals’ biological ages often differ from chronological (i.e. actual) ages, raising the possibility that biological age could be a better predictor of age-related perinatal morbidity. A robust method of calculating biological age is the Epigenetic Clock, which determines an individual’s Epigenetic Age based on their specific DNA methylation patterns (common epigenetic modifications). Epigenetic Age has been shown to better predict morbidity or mortality over chronological age and epigenetic aging is also associated with social adversity and stress exposure. Given that social and economic stressors contribute to poor maternal outcomes (as evidenced by maternal health disparities), it is possible that epigenetic age is also a key mediator of birth related morbidity. Therefore, I will test the central hypothesis that epigenetic age will predict impaired uterine function more accurately than maternal chronological age (years) and that greater epigenetic age is associated with higher indices of psychosocial/ socioeconomic stressors during pregnancy. The career development goal of this application is to gain proficiency in genome wide epigenetic methods and epigenetic clock specifically in addition to expanding my training to include health disparities research methods. In this proposal, I seek to integrate these scientific fields and advance knowledge of the role of the environment on maternal health and morbidity related to childbirth and uterine function. In the first aim, using bio-banked tissues, I will apply Epigenetic Clock methods to extracted DNA from maternal uterine and blood samples to compare epigenetic age across tissue types and correlate with uterine mRNA for proteins responsible for uterine contractility and function during labor. In the second aim, I will use banked data and tissue from a large nationally representative sample of young (18-25 yo) and advanced age women (>35 yo). I will apply the Epigenetic Clock method to these DNA samples to 1) understand the relationship between phenotypes of socioeconomic and psychosocial stress (using mixture modeling) and epigenetic age in maternal blood and 2) examine the role of epigenetic age and uterine dysfunction during labor leading to greater maternal morbidity (prolonged labor leading to cesarean delivery, failed induction or postpartum hemorrhage). Finally, I will explore how maternal epigenetic age relates to infants’ gestational age and his/her own epigenetic age. Together, this study will advance our knowledge of how epigenetic aging can influence perinatal morbidity in the context of the maternal environment.

高龄妇女（50 ~ 35岁）在妊娠期出现不良后果的风险明显更高