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

项目摘要 我们对自发性早产（SPTB）的机制的理解存在重大差距， 非西班牙裔（NH）黑人女性。早产（<37周妊娠）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，身体和社会风险增加 残疾人与他们的长期同行相比。黑人女性比其他女性多一倍 竞相早产17-α-羟孕酮己酸酯（17 P）可预防某些患者的复发性SPTB 女性，但与NH白色女性相比，对NH黑人的有效性较低。这个变量的原因 人们对反应能力了解甚少，这是一个重大的知识差距。长期目标是 研究的目的是确定有17 P无反应风险的NH黑人妇女，为她们提供替代疗法， 从而降低复发性SPTB的风险。这里的目的是量化一氧化氮（NO）的作用 接受17 P治疗的NH黑人女性中复发性SPTB的病理生理学途径。我们的中央 一种假设是，NO通路异常使NH黑人妇女对17 P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已发表的文献， 母体基因型、母体血液来源和胎盘来源的蛋白质组学谱和DNA甲基化， NO途径在注定成为17 P无应答者妇女中不同。此外，我们的研究表明， NO途径基因存在强烈的种族差异。这项工作的理由是，它将提供新的见解， 增加对SPTB对17 P无反应的病理生理学和生物学机制的理解 在NH黑人妇女中进行预防，这是一个17 P治疗失败风险不成比例高的群体。的 中心假设将通过追求三个目标进行测试：（1）确定NO途径中的哪些基因是 在注定成为17 P无应答者的妇女中，在中期妊娠中差异表达，（2）建立 在17 P无应答者中，哪种NO途径基因在中期妊娠期显示差异CpG甲基化，以及 (3)量化母亲和后代之间基因表达和表观遗传标记的保守性。这些 将使用来自300名NH黑人妇女的纵向样本评估目标。这种方法是创新的， 因为这个项目将检查母体循环血液和胎儿中的表观遗传和表达变化， 衍生的组织响应于17 P，阐明响应于17 P发生的急性变化。的 提出的研究是重要的，因为甲基化和基因表达模式是可识别的， 在妊娠中期，它们可以为诊断测试的发展提供基础，以确定有风险的妇女， 尽管17 P预防，但仍复发PTB。该项目直接与NIMHD的使命保持一致，并将 提供即时和持续的临床和公共卫生影响，以减少PTB的差异 在NH黑人妇女和婴儿的结果，从而降低新生儿死亡率和终身发病率。

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.