The research proposed in this PERC (renewal) grant application is based upon three repositions, the evidence for which is formidable: (i) Prostaglandin, produced in uterus, is the agent that causes the initiation and progression of labor. (ii) The biomolecular events of parturition are remarkably similar in all mammalian species despite known differences among these in endocrine physiology before labor. (iii) The maintenance of pregnancy and thence the initiation of labor are closely aligned by way, a paracrine system established between fetus and decidua vera. We suggest that uterine decidual development, function, and PGF2 alpha secretion are regulated by way of fetal contributions to this paracrine system, which likely is progesterone-dependent. Accordingly, modifications (physiologic or pathologic) of paracrine or endocrine support causes labor. To evaluate these hypotheses experimentally, we will investigate the infrastructure of the biomolecular processes that promote uterine prepareness for labor in all species, viz., contractile responsiveness to uterotropic agents, ap junction formation between myometrial cells, and oxytocin receptors (Project 1). A well as the antecedent event of labor: cervical softening and ripening (Project 2). The specifications of the putative progesterone-dependent paracrine system that functions to inhibit decidual PGF2 alpha formation will be defined (Project 3) as will the coordinated regulation of arachidonic acid mobilization and the formation of bioactive intermediates (platelet-activating factor and prostaglandins) in fetal membranes and uterine decidua vera (Project 4). We will explore the proposition that the fetus (and fetal products) contribute to the paracrine system to promote growth and maturational processes in fetal membranes and decidua (Projects 3- 5); and, we will test the hypothesis that infection-associated preterm labor is a model that can provide important clues helpful for an understanding of spontaneous labor at term (Projects 2-5). We will continue to define the regulation of fetal adrenal function and the endocrine physiology of human and ovine pregnancy (Project 6). The proposed fetus-amniotic fluid-fetal membrane-decidua paracrine system, as well as the uterine cervical and myometrial maturation systems will be investigated as endocrine dependent processes (Projects 1-6). We suggest that an organ communication system exists between fetus, amniotic fluid, fetal membranes, decidua vera, and myometrium, one that is elementary to the maintenance of pregnancy and the initiation of labor.
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