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

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 环境对孕产妇健康和与孕产妇死亡有关的发病率的作用 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。

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.