This program contains three integrated projects and three well established scientific cores that continue this laboratory's testing of hypotheses fundamental to understanding fetal neuroendocrine maturation and parturition. The hypotheses are related to fetal endocrinology, placental and fetal membranes and decidual and myometrial regulation. In parallel experiments the present proposal will continue to utilize chronically instrumented pregnant sheep and non-human primates and its unique in several aspects (particularly in focussed efforts to correlate and compare work in ovine and non-human primate pregnancy). Integrated with whole animal studies will be molecular biology approaches, in vitro studies, biochemical, immunocytochemical, and endocrinological methods some of longstanding and some developed in years 06-10. The three projects use a multi-disciplinary approach in which selected single variables will be changed and results analyzed with appropriate statistical techniques. Project I continues the work conducted in Years 1-10 with on-human primates to obtain a better understanding of the integrated function of fetal and maternal neuroendocrine systems and the myometrium. It tests the overall function of prostaglandin (PG) on fetal and maternal hypothalamo- pituitary-adrenal (HPA) placental feedback and feed-forward loops. We will also investigate the role of CRH on uterine blood flow, myometrial activity and neuroendocrine function. Project II continues work performed in the previous funding period to study the integration of placental and fetal HPA axis (HPAA) function in chronically instrumented pregnant sheep. The proposed work addresses PG's role both as activators and/or stimulators of parturition at fetal and maternal hypothalamus, pituitary and adrenal as well as in placenta and uterine tissues, and the differential contribution of the two PG synthase isoforms on promotions of parturition of neuroendocrine function. Project III test the hypothesis that the fetal hippocampus plays a central role in regulating the fetal HPAA. The PI is the only investigator currently undertaking fetal stereotaxic neurosurgery in chronic whole animal investigations. We have taken note of the comments of the IRG in all projects. The specific responses are detailed within each project. Prematurity and complications of late gestation and 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 non-human primates.
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