Oligohydramnios (OH) is associated with fetal growth retardation, fetal distress during labor and neonatal morbidity. Intrauterine fetal stress has been associated with elevated fetal plasma and amniotic fluid (AF) vasopressin (VP) levels. This project will investigate the fetal endocrine regulation of amniotic fluid (AF) volume with the hypothesis that OH may result from chronic fetal VP hypersecretion. Initially the normal physiology of AF secretion (fetal lung fluid and urine production) and resorption (fetal swallowing ) will be studied. The effects of vasopressin on lung fluid and urine production and of VP and angiotensin-2 on fetal swallowing will be examined. In addition, the fetal endocrine response to volume/osmolar pertubations and the impact on AF will be explored. The above studies will provide necessary information for the development of an ovine model of OH. Experiments have been designed to directly assess the effect of chronically elevated fetal plasma VP on AF volume. Finally, the potential for therapeutic modulation of AF volume by the intraamniotic administration of specific VP agonists and antagonists will be examined. The candidate has a confirmed commitment to an academic career. He has considerable research experience and expertise with study design and analysis, the use of the chronically catheterized pregnant sheep model, and laboratory techniques including radioimmunoassay methods. The research environment provides excellent facilities while the combined obstetric and pediatric faculties provide exceptional expertise in perinatal physiology and endocrinology. In summary, this application, with the commitment of the institution and faculty, combines the techniques of the chronic ovine fetal model with the laboratory resources to investigate fetal neurohypophyseal hormone metabolism. The research plan will promote the development of a committed new investigator and has important human therapeutic interventions.
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