The long range objective of this application is to address an important biologic question: metabolic regulation of growth. It is hypothesized that the maternal metabolic environment, i.e. physiologic adaptation or perturbations due to nutrient modification or disease process (diabetes mellitus), regulates fetal growth. The proposed hypotheses are based upon data generated in the investigators' laboratories or in the PERC. State-of-the-art techniques, genetic and molecular biology in animal models, and stable isotope, mass spectrometry in humans will be applied. The proposed studies are a continuum documenting the maternal influences on fetal growth and neonatal adaptation, the fetal influence on maternal metabolism, and the long term consequences of fetal and neonatal metabolic/nutrient perturbations. Six projects are presented. The first two examine, in humans, the changes in maternal glucose and amino acid metabolism, resistance to insulin action and their relation to fetal/placental growth, and alterations in infants' growth and carbohydrate metabolism during the first year. It is hypothesized that insulin resistance and metabolism of non-essential amino acids may be important determinants of fetal growth. Project #3 examines the role of two environmental factors (diet and physical activity) and two hormones (HPL and fetal insulin) in placental growth. This study examines the hypothesis that early placental growth is a key determinant of fetal growth. Project #4 examines the mechanisms responsible for the metabolic """"""""imprinting"""""""" observed with early nutrient intervention in neonatal rat and extends the in-utero studies to the neonate. Project #5 examines the role of fetal insulin and human placental lactogen on fetal growth and metabolism in a binary transgenic mouse model. Project #6 examines a key event in relation to extrauterine adaptation and survival, i.e. appearance of hepatic gluconeogenesis by evaluating the factors responsible, e.g. nutrient supply, hepatic redox state, for the patterning of expression of the genes for cytosolic form of P- enolpyruvate carboxykinase. All projects are scientifically interactive, complement each other and utilize the core laboratories. The mechanistic questions are being addressed using sophisticated modern technologies in animal models. These studies will contribute to our understanding of metabolic/hormonal regulation of fetal growth and help develop therapeutic strategies for the disease states.
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