The single most effective predictor of preterm birth is the state of cervix upon presentation with symptoms of preterm labor. The mechanisms underlying physiological cervical ripening at term are largely unknown, and the causes of preterm cervical dilation are even more elusive. Our laboratory, together with complementary expertise from other projects in this application, has expanded its long-term strength in the biology and physiology of human parturition to include a more integrated approach to delve deeply into the molecular transcriptional and genomic mechanisms that underpin the physiology of normal labor at term and the pathophysiology of preterm birth. Here, we propose (i) to determine if ER antagonists block preterm cervical ripening and labor, (ii) to explore the global effects of PR- and ER-mediated signaling pathways in human cervical cells and the cellular mechanisms by which PRs inhibit ER-mediated signaling, and (iii) to determine the role of ER-mediated signaling pathways in cervical ripening and dilation in vivo.
PROJECT 3 NARRATIVE Preterm birth is the leading cause of infant mortality throughout the world. The overarching goal of this research is to enhance our understanding of the genes and regulatory mechanisms that mediate preterm cervical shortening during pregnancy and labor, a major cause of preterm birth. In the proposed research, we will use highly differentiated human cervical stromal cells and tissues and the pregnant guinea pig model to address the central roles of progesterone receptor (PR) and estrogen receptors (ER? and ER?) in maintenance of cervical competency and initiation of preterm cervical ripening, labor, and preterm birth. Next generation sequencing of RNA (RNA-seq), GRO-seq, combined with chromatin immunoprecipitation-deep sequencing (ChIP-seq) will be used to identify novel cervical genes and pathways that mediate premature cervical shortening and labor.
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