The integrated clinical and basic science research described in this PERC renewal application is designed to explore the regulation of the uterine phases of parturition and the mechanisms that provide for transitions from one phase to the next. We divide the parturition process, arbitrarily, into 4 phases that characterize the major functional states of the uterus during pregnancy. Uterine phase O is the time of uterine quiescence that occupies the first 95% of pregnancy (Projects III, IV, V). Phase 1 is the time of uterine preparedness for active labor when morphological and biomolecular changes develop in the uterus (Projects I, II, III) that enable the coordinated, forceful contractions of uterine phase 2 of parturition , i.e., the time of active labor (Projects I, III, IV, V). Uterine phase 3 of parturition begins after delivery and includes postpartum uterine hemostasis, lactation and milk let-down, and uterine involution. In sheep, some processes of phase 3 begin, as a result of progesterone withdrawal, even before delivery (Project V). In Project I, the evolution of three pregnancy- parturitional processes will be examined by way of clinically-based studies: (i) the relationship between parturition and inflammation : viz., are inflammatory mediators involved in the initiation of parturition at term or preterm; or rather, does labor beget inflammation?; (ii) the natural order of appearance of uterine phase 1 proteins in myometrium; and, (iii) a newly discovered biological system of the fetal amnion, i.e., the formation of a vasocontractant and a vasorelaxant that can be transported to the chorionic vessels. The biomolecular regulation of these processes will be defined in Project II; moreover, a unique form of progesterone withdrawal preceding human parturition will be explored: TGF-beta acts in a gene-specific manner to abolish progesterone action on the expression of specific genes in human myometrium and decidua. Studies are described in Project III to define the regulation of [Ca2+];i and Ca2+ flux (including sequestration, binding, and extrusion) in myometrial cells and tissue strips. The experiments are designed to define the biomolecular regulation of myometrial quiescence during uterine phase O. The synthesis, metabolism, and degradation of platelet-activating factor (PAF) in pregnancy and parturition are addressed in Project IV, with special attention given to (i) the role of fetal lung and kidney as sources of Paf in amniotic fluid and (ii) a definition of the source of PAF-acetylhydrolase in maternal plasma during pregnancy. In Project V, the molecular regulation of 3beta-HSD in human and sheep placenta and human fetal adrenal and that of P45017alpha in sheep placenta is addressed. The P45017alpha genes of human and sheep will be compared to ascertain if differences in 5'-regulatory sequences account for differences in placental P45017alpha expression in the 2 species. We seek to define the biomolecular particulars of human parturition in search of a solution to the problem of preterm birth, which we consider to be one of the major health hazards of humans.
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