DIAGNOSTIC MARKERS FOR EARLY DETECTION AND TREATMENT OF PRETERM PREGNANCIES

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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.