Intrauterine growth retardation is a significant cause of perinatal morbidity and mortality. Maternal conditions which results in reduced uteroplacental blood flow are consistently associated with fetal growth retardation. The fetal metabolic adaptations which occur under these conditions ensure survival of the fetus at he expense of growth. The purpose of the present investigation is to elucidate the mechanisms responsible for the adaptations which impact on fetal growth. The proposed studies will examine the following hypotheses: 1) fetal hypoxia due to uteroplacental blood flow reduction will decrease tissue insulin like growth factor I (IGF-I) bioactivity which in turn will effect a decrease in protein synthesis and accretion in selected tissues (skeletal muscle), resulting in deceleration in growth rate. 2) the changes in IGF- I bioactivity and protein metabolism can be reserved, at least in part, through maternal (and thereby fetal) oxygen supplementation. 3) infusion of IGF-I into the fetal hindlimb will result in increased protein synthesis in skeletal muscle tissue. These hypotheses will be tested using a model of prolonged uteroplacental blood flow reduction in the sheep developed by the candidate. Daily measurements of linear fetal growth will be made before and during 14 days of uteroplacental blood flow reduction during which time the rates of protein synthesis, breakdown, oxidation and net accretion in the whole fetal body as well as in fetal skeletal muscle will be determined using stable and radioactive tracer methodology. Skeletal muscle metabolism will be examined using an in vivo fetal hindlimb. These studies will provide a broader understanding of the metabolic processes which contribute to the development of fetal growth retardation, thereby possibly stimulating new approaches to the prevention and treatment of this condition in human pregnancies.
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