The Pharmacoepigenomics of Recurrent Preterm Birth in Non-Hispanic Black Women

项目总结 我们对自发性早产(SPTB)发生机制的理解存在严重差距 非西班牙裔(NH)黑人女性。早产(妊娠37周)是导致死亡的主要原因 在非异常新生儿中，幸存者终身智力、身体和社交方面的风险增加 残疾人与他们的同龄人相比。NH黑人女性患病的可能性是其他女性的两倍 竞相早产。17-羟孕酮己酸酯(17P)预防部分SPTB复发 但与NH白人女性相比，NH黑人女性的效果较差。产生这种变数的原因 人们对响应性知之甚少，这代表着一种关键的知识差距。这样做的长期目标是 研究旨在确定NH黑人女性有17P无反应的风险，为她们提供替代治疗， 从而降低肺结核复发的风险。这里的目的是量化一氧化氮(No)的作用。 接受17P治疗的NH黑人妇女中复发SPTB的病理生理学途径。我们的中央 假说是，NO通路的异常使NH黑人女性对17P无反应 预防复发性肺结核。这一假设是基于我们的初步数据和出版的文献显示的 母体基因、母体血液和胎盘来源的蛋白质组谱以及DNA甲基化 在注定成为17P无反应者的女性中，NO途径有所不同。此外，我们的研究表明 NO途径基因存在较强的种族差异。这项工作的基本原理是它将提供新的见解和 对SPTB对17P无反应的病理生理和生物学机制有了更深入的了解 NH黑人妇女的预防，这是一个17P治疗失败风险不成比例的群体。这个 中心假说将通过追求三个目标来检验：(1)确定NO途径中的哪些基因是 在注定为17P无应答者的妇女中，在中期表达的差异，(2)确定 在17P无应答者中，哪些途径基因在中期表现出不同的CpG甲基化，以及 (3)量化母子间基因表达和表观遗传标记的保守性。这些 AIMS将使用300名NH黑人妇女的纵向样本进行评估。这种方法是创新的， 因为这个项目将检查母亲循环血液和胎儿体内的表观遗传和表达变化- 17P对衍生组织的反应，揭示了对17P反应发生的剧烈变化。这个 拟议的研究具有重要意义，因为甲基化和基因表达模式在 在怀孕中期，它们可能为开发诊断试验提供基础，以确定妇女患上糖尿病的风险 尽管进行了17P预防，但仍复发了肺结核。该项目直接与NIMHD的使命相一致，并将 提供直接和持续的临床和公共卫生影响，以减少肺结核的差异 减少NH黑人妇女和婴儿的结局，从而降低新生儿死亡率和终生发病率。

PROJECT SUMMARY There is a critical gap in our understanding of mechanisms that underlie spontaneous preterm birth (SPTB) in non-Hispanic (NH) black women. Preterm delivery (<37 weeks gestation) is the leading cause of mortality among non-anomalous neonates; survivors are at increased risk for lifelong intellectual, physical, and social disabilities compared with their term counterparts. NH black women are twice as likely as women of other races to deliver preterm. 17-alpha hydroxyprogesterone caproate (17P) prevents recurrent SPTB in some women, but is less effective for NH black compared with NH white women. The reasons for this variable responsiveness are poorly understood, and represent a critical knowledge gap. The long-term goal of this research is to identify NH black women at risk for 17P non-response, provide them with alternate therapies, and thereby reduce the risk of recurrent SPTB. The objective here is to quantify the role of nitric oxide (NO) pathways in the pathophysiology of recurrent SPTB among NH black women receiving 17P. Our central hypothesis is that aberrations in the NO pathway predispose NH black women to 17P non-response for the recurrent SPTB prevention. This hypothesis is based on our preliminary data and published literature showing maternal genotype, maternal blood-derived and placental-derived proteomic profiles, and DNA methylation in the NO pathway differ among women destined to be 17P non-responders. Furthermore, our studies show strong race-disparity in NO pathway genes. The rationale for this work is that it will provide new insight and increased understanding into the pathophysiology and biologic mechanisms of non-response to 17P for SPTB prevention among NH black women, a group at disproportionately high risk of 17P treatment failure. The central hypothesis will be tested by pursuing three Aims: (1) Determine which genes in the NO pathway are differentially expressed in the mid-trimester among women destined to be 17P non-responders, (2) Establish which NO pathway genes display differential CpG methylation in the mid-trimester in 17P non-responders, and (3) Quantify conservation of gene expression and epigenetic markers between mother and offspring. These aims will be assessed using longitudinal samples from 300 NH black women. This approach is innovative, because this project will examine epigenetic and expression changes in maternal circulating blood and in fetal- derived tissues in response to 17P, shedding light on acute changes that occur in response to 17P. The proposed research is significant because as methylation and gene expression patterns are recognizable in the second trimester, they may provide the basis for development of diagnostic tests to identify women at risk for recurrent PTB despite 17P prophylaxis. This project is directly aligned with the mission of the NIMHD, and will provide immediate and sustained clinical and public health impact to reduce disparities in PTB outcomes in NH black women and infants, thereby reducing neonatal mortality and lifelong morbidity.