As preterm labor is the major cause of perinatal morbidity and mortality and imposes a huge financial and emotional burden on society, increasing our basic knowledge of the mechanisms whereby the uterus changes from a quiescent organ to one capable of coordinated contractile activity to expel the fetus at term should give us important information towards understanding why labor sometimes begins prematurely. We will test the hypothesis that changes in progesterone and estrogen action either mediated via expression of their specific receptors or by a membrane-mediated mechanism lead to changes in both the type and quantity of eicosanoid produced by myometrium at labor and to changes in receptors for these eicosanoids on the uterus. Studies will utilize human myometrial tissue obtained both at term or preterm from patients either in or not in labor. Ontogenetic studies will be performed in rats from day 16 to 22 (delivery) together with studies using 3 models of preterm labor in the rat. We will investigate: 1. Changes in expression and concentrations of estrogen and progesterone receptor (measured by northern analysis and immunoassay) in relation to both peripheral plasma and myometrial tissue steroid concentrations in term and preterm labor and in response to hormonal treatment. 2. Changes in both the type and quantity of eicosanoids (PG's, LT's, HETE's and EET's) produced by myometrium in term and preterm labor and the effect of steroids, in vivo and in vitro, on overall eicosanoid synthesis and expression and activity of key enzymes. 3. Characterization of eicosanoid receptors on human and rat myometrium and changes in receptor concentration and affinity which occur either with term or preterm labor or in response to hormonal manipulation. 4. Alterations in myometrial plasma membrane fluidity which occur with term or preterm labor or following hormonal manipulation as an indicator of a steroid-mediated alteration in membrane activity. Our overall objective is to relate the alterations in steroid concentrations, steroid-receptor interactions and steroid-induced membrane fluidity changes to alterations in eicosanoid synthesis and action which occur in term or preterm labor. It is important to define more clearly the mechanism underlying changes in steroid concentration and action, thought to be the key to control of myometrial activity, with that of eicosanoid synthesis and action, thought to be an effector of contractility.
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