This program contains three integrated projects, three well established scientific cores and two subcontracts that continue our testing of hypotheses fundamental to our understanding of fetal neuroendocrine maturation and parturition. These hypotheses are related to fetal neuroendocrinology, placental and fetal membranes as well as decidual, myometrial and cervical regulation. In parallel experiments we will continue to utilize, chronically instrumented pregnant sheep and rhesus monkeys. We believe this program is unique in several aspects (particularly in our focussed efforts to correlate and compare work in ovine and nonhuman primate pregnancy). In conjunction with our whole animal studies, we now propose molecular biology approaches, in vitro studies and sophisticated cellular techniques in addition to an expanding repertoire of biophysical, biochemical, immunocytochemical, and endocrinological methods developed through and since the previous funding period. We propose a multidisciplinary approach in which selected single variables will be changed and results analyzed with appropriate statistical techniques. Project I continues our use of nonhuman primates to obtain a better understanding of fetal neuroendocrinology and the myometrium. It tests the hypothesis that the fetus plays a major role in the initiation of parturition in nonhuman primates using parallel mechanisms to those demonstrated in sheep. We have developed a multi-methodological approach to test the hypothesis that the periodic switch from contractures to contractions that we have demonstrated in two different nonhuman primates is caused by changes in arachidonic acid metabolism of decidua and myometrium, changes in receptors, expression of key genetic messages, and ion channel function. In addition, we hypothesize that similar changes are responsible for normal cervical dilation. Project II continues work performed in the previous funding period to study fetal hypothalamic maturation in sheep. In our previous period of funding we demonstrated the critical role of the paraventricular nuclei (PVN) in the initiation of parturition. Project II will test the hypothesis that catecholaminergic brain stem afferents and hippocampal afferent inputs to the fetal ovine PVN play a key role in fetal responses to hypoxemia and the initiation of labor. Project III tests the hypothesis that alterations in expression of CRH and AVP gene in the fetal PVN and changes in glucocorticoid feedback and receptor population in the fetal PVN play important roles in fetal hypothalamic maturation in relation to ACTH production that leads to fetal adrenocortical development and subsequent parturition. Prematurity and complications of delivery are major obstetric problems with a profound effect on perinatal mortality and morbidity. Prematurity has a disproportionate effect on, and incidence in, minority women. Our proposed experiments will define similarities and differences between sheep and nonhuman primates. We will use the strength of these differences to unlock fundamental mechanisms. There is a need to combine whole animal studies with cellular approaches to bring together the somewhat fragmented information available in pregnant women.
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