Preterm birth, the major cause of neonatal morbidity and mortality in the U.S., has increased steadily over the past two decades and now approaches ~13% of all live births. This alarming trend is due, in part, to our incomplete understanding of the pathways that maintain cervical integrity and uterine quiescence throughout pregnancy as well as those that promote cervical ripening and increased uterine contractility leading to labor. There is increasing evidence that both term and preterm labor are associated with an inflammatory response and that this is prevented throughout most of pregnancy by the anti-inflammatory actions of progesterone (P4) acting through it nuclear receptor (PR). The central theme of this proposal remains the elucidation of the molecular and cellular mechanisms that lead to the initiation of parturition, both at term and preterm. This theme is based on the overall hypothesis that the initiation of spontaneous labor in humans and in other mammals, is caused by a concerted series of biochemical and molecular events that culminate in an upregulation of inflammatory response pathways and a decrease in PR function. Although, preterm labor may have numerous causes, we propose that the signaling pathways that promote premature increase in uterine contractility, cervical ripening and expulsion of the fetus are similar to those at term. Thus, understanding the mechanisms leading to parturition at term should provide important insight into the development of therapeutic strategies to block these signaling mechanisms and prevent preterm labor. To achieve these goals, four interrelated projects and two cores are proposed. The goals of these Projects are: (1) To further define the genetic and epigenetic mechanisms whereby P4/PR inhibits myometrial contractility during pregnancy and by which inflammatory signaling upregulates contractile genes and represses PR function leading to labor, (2) to enhance our understanding of the role of hyaluronan (HA) in cervical ripening through elucidation of the effects of cervix-specific gene targeting of the key regulatory enzyme, hyaluronan synthase 2, and altered expression of HA degradative enzymes, hyaluronidases, (3) to elucidate the regulation of cervical ripening and dilation through a transcriptional network involving PRs, ERs, and the novel cervical transcription factor MiTF-CX, and (4) to test the hypothesis that physiological and pathological inflammatory responses in the uterus and cervix during pregnancy and parturition share a common set of molecular events that play crucial roles in the physiology of preterm and term parturition. We propose that these interrelated projects, carried out by a highly interactive research team, will achieve the long-range goals of this Program and contribute to a reduction in the incidence of preterm birth. PUBLIC HEALTH RELEVANCE : Premature births are the major cause of neonatal morbidity and mortality in the developed world. Identification of mechanisms that initiate parturition should lead to new insights into the pathophysiology of preterm birth and strategies to prevent it and its devastating consequences.