Igf Binding Proteins in Perinatal Growth

Chernausek, Steven

Abstract

The insulin-like growth factors (IGFs) are thought to be important regulators of perinatal growth. In vitro, the biologic activity of the IGFs is modulated by the insulin-like growth factor binding proteins (IGF- BP), a family of secreted proteins that complex with the IGFs. The long- term objective of this proposal is to test the hypothesis that the IGF-BPs critically influence IGF action during perinatal life. In the rat, the effects of epidermal growth factor (EGF)-induced growth retardation and uteroplacental insufficiency on the expression of IGF-BP- 1,2 ,3 and IGF-I and IGF-II will be examined. Expression will be measured by radioimmunoassays, ligand blot and RNA blot hybridization. The effects of increased IGF-BP expression on plasma IGF metabolism will be addressed by injecting radiolabeled IGFs into normal or growth-retarded rats. IGF- BP-3 will be injected to determine the effect of elevated BP3 on IGF half- life and animal growth. These experiments will determine whether IGF-BPs modulate the actions of IGFs and whether some of the factors that influence perinatal growth also alter the expression of IGF-BPs. Finally, the regulation of the IGF-BP will be studied by assessing the effects of nutrition and insulin on the expression of the IGFs and IGF-BPs. In the human, the relationship of perinatal growth to IGF-BP expression will be addressed through a prospective, longitudinal study. Normal and intrauterine growth retarded (IUGR) infants will be examined at periodic intervals over the first 3 years of like and blood obtained for radioimmunoassay of IGF-BP-1, 2, 3 and IGF-I and IGF-II. It is hypothesized that plasma BP-1 concentrations will be elevated in IUGR infants and correlate with indices of nutritional status. It is anticipated that postnatal growth rate correlate with the BP-3:BP-1 ratio. Study of the IGF-BP system during the perinatal period will increase our understanding of the physiologic role of the IGFs and IGF-BPs in normal and aberrant perinatal growth. Greater knowledge of these processes is important because IUGR is frequently associated with permanent sequelae. Up to 50% of infants born small for gestational age remain growth-retarded and many have impaired intellectual development. Ultimately, more complete understanding of IGF/IGF-BP function could lead to strategies to identify infants at risk for permanent sequelae or to therapies to ameliorate the growth-retarded state.