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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

基本信息

批准号：
10630244
负责人：
Elise N Erickson
金额：
$ 24.9万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-24 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630244
关键词：
Acceleration Age Age Years Aging American Binding 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 Health Disparities Research High Risk Woman Impairment Individual Induced Labor Infant Knowledge Link Longevity Maternal Health Maternal Mortality Measures Mediator 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 Ticks Tissues Training Umbilical Cord Blood United States Uterus Woman Work adverse outcome age group age related biobank 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 social adversity social stress socioeconomics stressor tool uterine contractility young woman

项目摘要

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（> 35岁）在接受治疗期间发生不良结局的风险显著较高。与年轻女性相比，这一问题既严重又日益严重，因为出生人数在过去40年里，这一年龄组的产妇死亡率增加了9倍，产妇发病率上升，死亡率在美国。鉴于产程延长，剖腹产和产后出血更为常见在老年妇女中，随着年龄的增长子宫功能（收缩力）下降可能是分娩的一个来源- 相关功能障碍。先前的研究表明，个体的生物学年龄通常与时间年龄不同， (i.e.实际）年龄，提高了生物学年龄可能是年龄相关围产儿死亡的更好预测因子的可能性。发病率计算生物学年龄的一种可靠方法是表观遗传时钟，它确定了一个人的年龄。基于其特定DNA甲基化模式的个体表观遗传年龄（常见表观遗传年龄）修改）。表观遗传年龄比实际年龄更能预测发病率或死亡率表观遗传衰老也与社会逆境和压力暴露有关。鉴于社会和经济压力因素导致孕产妇结局不佳（孕产妇健康差异就是证明），表观遗传年龄也可能是出生相关发病率的关键介导因素。因此，我将测试中央假设表观遗传年龄比母体年龄更准确地预测子宫功能受损实足年龄（岁），更大的表观遗传年龄与更高的心理社会/ 怀孕期间的社会经济压力。此应用程序的职业发展目标是获得熟练掌握基因组范围的表观遗传方法和表观遗传时钟，特别是除了扩大我的培训包括健康差距研究方法。在这份提案中，我试图将这些科学的领域并深入了解环境对孕产妇健康和与孕产妇相关的发病率的作用分娩和子宫功能。在第一个目标中，使用生物银行组织，我将应用表观遗传时钟方法从母体子宫和血液样本中提取DNA，比较不同组织类型的表观遗传年龄，与子宫mRNA相关的蛋白质负责子宫收缩性和功能在劳动。在第二个目标是，我将使用来自全国具有代表性的年轻人（18-25岁）样本的银行数据和组织年龄> 35岁）和高龄女性（>35岁）。我将应用表观遗传时钟方法对这些DNA样本1）了解社会经济和心理社会压力表型之间的关系（使用混合模型）和表观遗传年龄在母体血液中的作用，以及2）检查表观遗传年龄和子宫产程中的功能障碍导致更高的产妇发病率（延长的产程导致剖腹产，引产失败或产后出血）。最后，我将探讨母亲的表观遗传年龄如何与婴儿的胎龄和他/她自己的表观遗传年龄。总之，这项研究将促进我们对表观遗传衰老如何影响围产期发病率在孕产妇环境的背景下。