DIAGNOSTIC MARKERS FOR EARLY DETECTION AND TREATMENT OF PRETERM PREGNANCIES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 早产(37周前)约占所有妊娠的10%-12%，这一发生率在过去几十年中没有显着变化。尽管在围产期和新生儿护理方面取得了进展和改善，但早产仍然是围产期发病率和死亡率的最重要原因。在我们努力降低这种早产风险的过程中，最关键的限制是对“过早”激活的信号转导通路的了解不足。此外，多种病因和缺乏充分模拟人类妊娠和分娩的动物模型阻碍了这一领域的进展。使用药物，如宫缩药物来调节子宫收缩或使用抗生素都不成功。有几条证据，如有早产史的风险增加和细胞因子的多态性，支持自发早产和分娩的遗传易感性。人类基因组序列和系统方法在生物学和医学中的应用有望在未来几年改变医学实践，使其从反应性学科(病人生病后做出反应)转变为预测性、个性化和预防性的模式。这在一定程度上将通过使用血液进行早期诊断来识别与临床前疾病状态相关的分子特征来实现。表观遗传网络平衡的破坏(组蛋白尾部修饰和DNA甲基化)与包括癌症在内的几个主要病理过程有关。在临床检测疾病状态之前，可以在血液中检测到异常的DNA甲基化。最近，表观遗传改变被证明在分娩的开始中起着关键作用。虽然已经描述了早期人类胚胎到囊胚期的全球DNA甲基化变化，但没有关于人类妊娠每三个月期间胎盘发生表观遗传学变化的信息。这项提议将检验这样一个假设，即启动子超甲基化导致的特定基因沉默调节了导致早产的不同调控途径，这些基因启动子区域的甲基化DNA可以预测容易早产和分娩的女性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Preterm delivery (before 37 weeks) occurs in approximately 10-12% of all pregnancies and this incidence has not changed significantly over the past few decades. Despite the advances and improvements in perinatal and neonatal care, preterm delivery is still the most important cause of perinatal morbidity and mortality. The most critical limitation in our efforts to decrease this risk of preterm delivery is inadequate understanding of the signal transduction pathways that are 'prematurely' activated. Moreover, multiple etiologies and a lack of an animal model that adequately mimics human gestation and parturition have impeded progress in this field. The use of pharmacological agents such as tocolytics to modulate uterine contractions or the use of antibiotics has not been successful. Several lines of evidence such as increased risk with a history of preterm delivery and polymorphisms in cytokines support a genetic predisposition to spontaneous preterm labor and birth. The availability of the human genome sequence and systems approach to biology and medicine promises to transform the practice of medicine over the next few years moving it from reactive discipline (responding after patient is sick) to a predictive, personalized and preventive mode. This will be achieved, in part, by early diagnostics using blood to identify molecular signatures associated with the pre-clinical onset of disease state. The disruption of balance of epigenetic networks (histone tail modifications and DNA methylation) has been implicated in several major pathologies including cancer. Aberrant DNA methylation can be detected in blood before clinical detection of the disease state. Recently, epigenetic alterations have been shown to play a critical role in the onset of labor. Although global DNA methylation changes in early human embryos up to the blastocyst stage have been described, there is no information on epigenetic changes occurring in the placenta during each trimester of human gestation. This proposal will test the hypothesis that specific genes silenced by promoter hypermethylation modulate distinct regulatory pathways that lead to preterm deliveries and methylated DNA in the promoter regions of these genes can predict women who are susceptible to preterm labor and delivery.