In the adult, growth is coordinated by the hypothalamo-pituitary axis. A signal to grow is transmitted to peripheral tissues via growth hormone which stimulates production of insulin-like growth factor I (IGF-I). IGF- I, produced in the liver and in several other tissues, mediates many growth-promoting actions through classical endocrine and paracrine mechanisms. In the fetus, IGF-I from several different tissues are believed to be important in regulating growth, but the signal that coordinates IGF-I synthesis and action is unknown. The hypothesis to be explored in this investigation is that the placenta and fetal liver regulate plasma concentrations of IGF-I and thus coordinate fetal growth. The rationale for this hypothesis is that the placenta and liver are perfused with 100% and 50% of oxygen and nutrients, respectively, derived from the maternal circulation before they reach other fetal tissues; there are large positive and negative arteriovenous concentration differences for IGF-I across both circulations that vary with oxygen and nutrient supply; and the magnitude of blood that flows to these organs is large, 40% and 25% of total cardiac output, respectively. Taken together, the placenta and liver are ideally situated to signal the fetus to grow when conditions are optimal by changing plasma IGF-I concentrations by rapidly altering the production and clearance of IGF-I or its specific binding proteins. To test the proposed hypothesis, several studies are planned. The effects of altered nutrient and oxygen delivery on plasma IGF-I concentrations, IGF-I metabolic clearance rate, production rate, and half-life, hepatic placental production and clearance rates of IGF-I and binding proteins will be determined. Studies will be performed in chronically-maintained preparations of fetal sheep with catheters in the aorta, umbilical and hepatic veins. Blood flows will be determined with the radionuclide- labeled microsphere technique. IGF-I and binding proteins will be quantitated by radioimmunoassay, electrophoresis. ligand blot, Northern blot, and in situ hybridization techniques. The information obtained from this investigation will clearly define the regulation of IGF-I and binding proteins in the fetus and provide further insight into our understanding of normal and abnormal intrauterine growth.
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