EXCEED THE SPACE PROVIDED. Hypoxia during the perinatal period and during early infancy is a significant cause of mortality and morbidity. Adrenocortical hormones are a vital component of the adaptation to hypoxic stress. Furthermore, neonatal hypoxic hyperlipidemia is a significant clinical entity, and changes in specific lipid metabolites alter adrenal function. The long-term objective of this proposal is to characterize the short and long-term consequences of perinatal hypoxia on the control of the hypothalamic-pituitary-adrenal (HPA) system and lipid metabolism in the rat.
Specific Aims 1 and 2 will evaluate the effect of neonatal hypoxia on the control of the hypothalamic-pituitary-adrenal axis by evaluating intracellular and systemic controllers of steroidogenesis, the timing and mechanisms of the stress-hyporesponsive period (SHRP), and the negative feedback control of CRH and POMC expression and ACTH release.
Specific Aim 3 will characterize the long-term sequellae of perinatal hypoxia by evaluating subsequent HPA responses to stimuli in the adult rat.
Specific Aim 4 will more fully characterize neonatal hypoxic hyperlipidemia by analyzing the interaction of neonatal hypoxia and glucocorticoid therapy, and by performing metabolomic analysis. Neonatal hypoxia from birth is accomplished by exposing newborn rats (with their lactating dams) to a hypoxic environment. Perinatal hypoxia is accomplished by exposing late-gestational pregnant rats to hypoxia and allowing them to deliver in a hypoxic environment. Physiological, biochemical and molecular assessment of adrenocortical function is performed by ACTH injection in vivo, using dispersed cells, evaluating StAR and PBR expression, and measuring CBG and glucocorticoid clearance. Hypothalamic-pituitary function is assessed by measuring stress- and CRH-induced ACTH release, by evaluating feedback sensitivity, and by analyzing pituitary, hypothalamic, and hippocampal function and pertinent receptor/hormone expression. Metabolic function is assessed by analysis of hepatic enzyme activity, as well as complete metabolomic analysis of serum and hepatic lipids. Characterization of the hypothalamic-pituitary-adrenal and metabolic adaptations to perinatal hypoxia can lead to new diagnostic approaches and therapies to minimize morbidity and mortality. PERFORMANCE SITE ========================================Section End===========================================

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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Malozowski, Saul N
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Medical College of Wisconsin
Internal Medicine/Medicine
Schools of Medicine
United States
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Bruder, Eric D; Taylor, Jennifer K; Kamer, Kimberli J et al. (2008) Development of the ACTH and corticosterone response to acute hypoxia in the neonatal rat. Am J Physiol Regul Integr Comp Physiol 295:R1195-203
Bruder, E D; Hoof, J Van; Young, J B et al. (2008) Epidermal growth factor and parathyroid hormone-related peptide mRNA in the mammary gland and their concentrations in milk: effects of postpartum hypoxia in lactating rats. Horm Metab Res 40:446-53
Raff, H; Jacobson, L; Cullinan, W E (2007) Augmented hypothalamic corticotrophin-releasing hormone mRNA and corticosterone responses to stress in adult rats exposed to perinatal hypoxia. J Neuroendocrinol 19:907-12
Raff, Hershel; Jacobson, Lauren (2007) Glucocorticoid feedback control of corticotropin in the hypoxic neonatal rat. J Endocrinol 192:453-8
Bruder, Eric D; Lee, Julie J; Widmaier, Eric P et al. (2007) Microarray and real-time PCR analysis of adrenal gland gene expression in the 7-day-old rat: effects of hypoxia from birth. Physiol Genomics 29:193-200
Bruder, E D; Henderson, L M; Raff, H (2006) Adrenal lipid profiles of chemically sympathectomized normoxic and hypoxic neonatal rats. Horm Metab Res 38:807-11
Raff, Hershel; Bruder, Eric D (2006) Adiponectin and resistin in the neonatal rat: effects of dexamethasone and hypoxia. Endocrine 29:341-4
Bruder, Eric D; Jacobson, Lauren; Raff, Hershel (2005) Plasma leptin and ghrelin in the neonatal rat: interaction of dexamethasone and hypoxia. J Endocrinol 185:477-84
Bruder, Eric D; Lee, Ping C; Raff, Hershel (2005) Lipid and fatty acid profiles in the brain, liver, and stomach contents of neonatal rats: effects of hypoxia. Am J Physiol Endocrinol Metab 288:E314-20
Bruder, Eric D; Lee, Ping C; Raff, Hershel (2004) Metabolic consequences of hypoxia from birth and dexamethasone treatment in the neonatal rat: comprehensive hepatic lipid and fatty acid profiling. Endocrinology 145:5364-72

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