Normal respiratory control in newborns, as in adults, is dependent upon neurotransmitter mediated interactions among networks of neurons comprising the brainstem respiratory centers. However, newborns are particularly prone to develop unstable respiratory patterns, suggesting important differences from adults in these interactions during the postnatal period. The long-range goal of this laboratory is to characterize excitatory and inhibitory central neuronal mechanisms which control autonomic nervous function, including respiratory drive, during the newborn period. The major objective of the present study is to characterize the effect of chronic prenatal hypoxia as a long-acting teratogen affecting inhibitory for transmitter metabolism, release and receptors. Opioid transmitters, including beta-endorphin and enkephalin, are associated with inhibition of respiratory drive, particularly in response to acute and severe hypoxia and other stresses. The present studies are to be performed in developing rats and include: 1) Identifying normal developmentally regulated mechanisms which affect availability of this class of transmitter for secretion. We will focus on glycosylation as a newly recognized mechanism regulating bioavailability of the peptides through regulation of post-translation processing of precursor peptide(s). 2) Determining the effect of prenatal hypoxemia on gene expression of the opioid precursors proopiomelanocortin and preproenkephalin, post-translation processing these precursor polypeptides, and creation of transiently increased bioactive beta-endorphin and enkephalin levels. And, 3) Characterizing the effects of prenatal maternal hypoxemia on long term regulation of opioid receptors in the newborn pup brainstem and specifically in neurons of the chemosensory pathway. Regular progression through defined developmental stages is crucial for normal development of the respiratory control system. Disruption of the normal developmental pattern due to an abnormal condition (e.g. hypoxia) during the perinatal period can lead to protracted system dysfunction possibly resulting in life threatening pathologies including apnea in premature infants, infantile apnea common in older infants, and Sudden Infant Death Syndrome.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG2-REB (02))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Gauda, E B; Lawson, E E (2000) Developmental influences on carotid body responses to hypoxia. Respir Physiol 121:199-208
Zahnow, C A; Panula, P; Yamatodani, A et al. (1998) Glucocorticoid hormones downregulate histidine decarboxylase mRNA and enzyme activity in rat lung. Am J Physiol 275:L407-13
White, L D; Lawson, E E (1997) Effects of chronic prenatal hypoxia on tyrosine hydroxylase and phenylethanolamine N-methyltransferase messenger RNA and protein levels in medulla oblongata of postnatal rat. Pediatr Res 42:455-62
Gingras, J L; Lawson, E E; McNamara, M C (1996) Developmental characteristics in the daily rhythm of norepinephrine concentration within rabbit brainstem regions. Reprod Fertil Dev 8:189-94
Gingras, J L; Lawson, E E; McNamara, M C (1995) Ontogeny of dopamine daily rhythms within rabbit brainstem regions. Biol Neonate 67:287-94
Czyzyk-Krzeska, M F; Furnari, B A; Lawson, E E et al. (1994) Hypoxia increases rate of transcription and stability of tyrosine hydroxylase mRNA in pheochromocytoma (PC12) cells. J Biol Chem 269:760-4
Kim, C S; McNamara, M C; Lauder, J M et al. (1994) Immunocytochemical detection of serotonin content in raphe neurons of newborn and young adult rabbits before and after acute hypoxia. Int J Dev Neurosci 12:499-505
Czyzyk-Krzeska, M F; Dominski, Z; Kole, R et al. (1994) Hypoxia stimulates binding of a cytoplasmic protein to a pyrimidine-rich sequence in the 3'-untranslated region of rat tyrosine hydroxylase mRNA. J Biol Chem 269:9940-5
White, L D; Lawson, E E; Millhorn, D E (1994) Ontogeny of the O2-sensitive pathway in medulla oblongata of postnatal rat. Respir Physiol 98:123-35
Millhorn, D E; Czyzyk-Krzeska, M; Bayliss, D A et al. (1993) Regulation of gene expression by hypoxia. Sleep 16:S44-8

Showing the most recent 10 out of 17 publications