This is a competitive renewal application for 5 years of funding to study the ontogeny and control of heme catabolism and bilirubin production in rats and newborn Rhesus monkeys, and to explore advanced and novel methods to measure carbon monoxide production in newborn infants as an indicator of risk for severe neonatal hyperbilirubinemia. As indicted in the abstract to the proposal, """"""""a better understanding of the role of increased bilirubin production in all kinds of neonatal jaundice and the prevention of hemolytic jaundice has remained an overall objective of the investigator's program. As a corollary, a more targeted, preventive approach to jaundice in high producers of the pigment, who may not be able to eliminate bilirubin fast enough to avoid high levels in circulation and tissues, is still needed. Control of bilirubin production is a logical strategy but has unexplored consequences for the immature animal. Thus, an increasing emphasis on studies to explore further, the pivotal role of heme oxygenase (HO) in developmental heme metabolism, is necessary. For this purpose, the specific aims are to: 1) continue in vitro and in vivo characterization and assessment of the metalloporphyrin inhibitors of HO and identify them as potential modulators of neonatal bilirubin production based on potent HO inhibition, negligible photoroactivity, desirable tissue distribution and elimination characteristics, and minimal side effects; 2) study the ontogeny of HO through measurements of mRNA, protein, and activity of HO in the liver, spleen, and intestine of the developing rat, and determine the effect of metalloporphyrin administration on this ontogeny; and 3) continue development of CO-monitoring technology for bedside diagnosis of hemolysis or increased total bilirubin production from other causes. The long term clinical application of the research proposal is """"""""to further develop a) non-invasive CO monitoring technology to identify neonates with high bilirubin production rates, and b) a safe and efficacious chemopreventive treatment regimen for infants at high risk for jaundice because of hemolysis."""""""" In support of the above specific aims, the investigators plan a wide- ranging series of studies designed to: 1) continue screening a variety of metalloporhyrins in vitro and in vivo for maximum efficacy and minimum side effects; 2) study the developmental ontogeny of the heme oxygenase enzyme system in various tissues from neonatal, suckling, and older rats, focusing on the intrinsic ontogeny of the heme oxygenase system and perturbations resulting from treatment with heme oxygenase inhibitors; and 3) further development and test instrumentation for non- invasive measurement of CO production in newborn infants, as an index of hemolysis or excess bilirubin production.
| Wong, R J; Vreman, H J; Schulz, S et al. (2011) In vitro inhibition of heme oxygenase isoenzymes by metalloporphyrins. J Perinatol 31 Suppl 1:S35-41 |
| Seidman, Daniel S; Moise, Jonathan; Ergaz, Zivanit et al. (2003) A prospective randomized controlled study of phototherapy using blue and blue-green light-emitting devices, and conventional halogen-quartz phototherapy. J Perinatol 23:123-7 |
| Meny, Robert G; Vreman, Hendrik J; Stevenson, David K et al. (2002) Failure to detect elevated levels of carboxyhemoglobin in infants dying from SIDS. J Forensic Sci 47:660-2 |
| Dennery, P A; Seidman, D S; Stevenson, D K (2001) Neonatal hyperbilirubinemia. N Engl J Med 344:581-90 |
| Stevenson, D K; Vreman, H J; Wong, R J et al. (2001) Carbon monoxide and bilirubin production in neonates. Semin Perinatol 25:85-93 |
| Vreman, H J; Wong, R J; Stevenson, D K (2001) Alternative metalloporphyrins for the treatment of neonatal jaundice. J Perinatol 21 Suppl 1:S108-13; discussion S125-7 |
| Seidman, D S; Moise, J; Ergaz, Z et al. (2000) A new blue light-emitting phototherapy device: a prospective randomized controlled study. J Pediatr 136:771-4 |
| Vreman, H J; Wong, R J; Kim, E C et al. (2000) Haem oxygenase activity in human umbilical cord and rat vascular tissues. Placenta 21:337-44 |
| Vreman, H J; Haenen, G R; Stevenson, D K et al. (2000) Reduction of the NO-mediated response in the rat aorta by metalloporphyrins. Can J Physiol Pharmacol 78:457-61 |
| Hayde, M; Pollak, A; Bernaschek, G et al. (2000) Association of fetal and maternal carboxyhemoglobin levels in normal and Rh-alloimmune pregnancies. Early Hum Dev 58:205-12 |
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