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

高龄女性(35岁)的不良后果风险显著增加。 与年轻女性相比，分娩。这个问题既很严重，而且还在不断增长，因为 发生在这个年龄段的人在过去40年里增加了9倍，增加了孕产妇发病率和 美国的死亡率。鉴于分娩时间过长，剖腹产和产后出血更为常见。 在老年女性中，随着年龄的增长，子宫功能(收缩能力)的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，个体的生物年龄通常与时间顺序不同 (即实际)年龄，增加了生物学年龄可以更好地预测与年龄相关的围产儿的可能性 发病率。一种可靠的计算生物年龄的方法是表观遗传时钟，它决定了 基于特定DNA甲基化模式的个体表观遗传年龄(常见表观遗传 修改)。表观遗传年龄被证明可以更好地预测超过实际年龄的发病率或死亡率 表观遗传衰老也与社会逆境和压力暴露有关。考虑到这一社会和 经济压力是导致产妇结局不佳的原因(从产妇健康差距中可以看出) 可能表观遗传年龄也是出生相关发病率的关键因素。因此，我将测试中央 表观遗传年龄将比母体年龄更准确地预测子宫功能受损的假设 年龄(年)，表观遗传年龄越大，心理社会指数越高。 孕期社会经济应激源。这份申请的职业发展目标是获得 精通全基因组表观遗传学方法和表观遗传学时钟，特别是在扩展我的 培训以纳入健康差距研究方法。在这项提议中，我试图将这些科学 关于环境对产妇健康的作用和与以下方面有关的发病率的领域和先进知识 分娩和子宫功能。在第一个目标中，使用生物库组织，我将应用表观遗传时钟方法 从孕妇的子宫和血液样本中提取DNA，以比较不同组织类型和 与子宫信使核糖核酸有关的蛋白质，负责子宫收缩和分娩期间的功能。在 第二个目标是，我将使用来自具有全国代表性的大样本青年(18-25岁)的银行数据和组织 YO)和高龄女性(35 YO)。我会将表观遗传时钟方法应用于这些DNA样本1) 理解社会经济压力和心理社会压力的表型之间的关系(使用混合体 建模)和母亲血液中的表观遗传年龄，以及2)检验表观遗传年龄和子宫的作用 分娩过程中的功能障碍导致更高的产妇发病率(延长分娩时间导致剖腹产， 诱导失败或产后出血)。最后，我将探讨母体表观遗传年龄与 婴儿的胎龄和他/她自己的表观遗传年龄。总而言之，这项研究将促进我们对 在母体环境的背景下，表观遗传老龄化如何影响围产儿发病率。

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.