Initiation of Human Labor: Prevention of Prematurity

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Successful parturition requires a sequence of events in myometrium and cervix that has been extensively studied over many years. Yet, preterm labor remains a significant complication of pregnancy, with severe individual and societal consequences. The molecular controls for the release of the uterine muscle from its protracted quiescent state and the remodeling of the cervix remain elusive. The long-range goals of this Program Project are to elucidate the molecular mechanisms regulating these processes, both in term and preterm labor. To this end, four projects are proposed. The first project addresses the potential role of the human fetal adrenal in parturition. Specifically, it will determine molecular mechanisms through which corticotropin-releasing hormone activates the fetal adrenal gland to cause a feed-forward cascade culminating in delivery of the fetus. Tissues and cells from human fetal adrenal neocortex and fetal zone will be used. The second project focuses on the physiological and biochemical events that cause an inflammatory response and negatively impact progesterone receptor (PR) function, based on postulates that uterine quiescence depends on increased PR transcriptional activity and NF-kappaB causes release from uterine quiescence. Specifically, the aims will define the role of surfactant proteins in the initiation of labor, their signaling mechanisms via NF-kappaB, mechanisms for the decline in coactivators in the term uterus, and progesterone and NF-kappaB regulation of target genes involved in myometrial quiescence/contractility, using both murine and human models. The third project explores the process of cervical remodeling, based on significant changes found in the matrix glycosaminoglycan hyaluronan (HA) coincident with cervical changes at term. Using murine models and human tissues, the aims will identify regulatory elements in the enzymes controlling HA synthesis and HA-binding proteins affecting HA function in the matrix; the hypothesis that this regulation is altered in women with cervical incompetence or preterm labor will be tested. In the fourth project the role of a specific transcription factor, MiTF, in cervical changes at term will be addressed, based on the finding that a novel tissue-specific isoform decreases dramatically with labor onset. The regulation of this isoform in human cervix and myometrium will be studied, including identifying positive and negative regulators of its transcriptional activation in specific cell types. Target genes of this transcription factor in cervical stromal cells will be identified. The investigators are a highly interactive research team, and the studies described in the four research projects are integrated and coordinated to achieve the long-range goals of this proposal.