This project proposes to study human placental metabolism, specifically energy and carbohydrate metabolism which are fundamental processes necessary to ensure normal fetal well being. The placenta favors oxidative phosphorylation under aerobic conditions, but its large glucose consumption and lactate production suggest glycolysis is also an important pathway. The relative importance of each pathway in normal and abnomal placentas is unknown. We would like to test the hypothesis that oxidative phosphorylation and glycolysis are both active metabolic pathways in normal placentas but that abnormal placentas, i.e., diabetic placentas, may favor increased glycolysis because of chronic exposure to high levels of glucose and localized hypoxia. Changes in energy metabolism in diabetic placentas may be associated with altered placental functions leading to clinically observed poor fetal outcomes. Placental metabolism studies will be performed using magnetic resonance spectroscopy (MRS) which observes dynamic biochemical processes noninvasively and continuously. MRS will be used to study placental villi within a perifusion apparatus. The villi are suspended in medium and viably maintained for several hours by continuous oxygenation, nutrient perifusion, pH and temperature control. Changes in ATP, inorganic phosphate, and sugar phosphate peaks representing ongoing oxidative phosphorylation and glycolysis will be observed. Tissue function will be evaluated by monitoring glucose and oxygen consumption, and lactate, lactate dehydrogenase, estradiol, progesterone and chorionic gonadotropin release. We will characterize the roles of oxidative phosphorylation and glycolysis in normal placentas under baseline conditions such as hypoxia, hyper and hypoglycemia, and acidosis. Responses to inhibitors such as cyanide and iodoacetate will be observed. We will perform spectroscopy of viable tissue as well as perchloric acid tissue extracts which yield better resolved spectra at fixed time points. After establishing villous behavior under normal and experimental conditions, diabetic placentas will be studied under similar conditions and comparative analysis performed. We hope to acquire a better understanding of normal and diabetic placental energy and carbyhydrate metabolism by using the powerful noninvasive method of MRS. Information gained will not only have potential clinical significance, but may also represent important complements to future in vivo spectroscopic studies of the placenta.
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