The aim of this research is the study of the maturation and regulation of the hepatic metabolism of bilirubin. Neonatal hyperbilirubinemia of human infants continues to be a significant morbidity risk and, at times, mortality risk. Clarification of its pathogenesis is required in order to prevent it or more effectively treat it. Three disorders of the enzymatic conjugation of bilirubin to its polar glucuronide by UDP-glucuronyl transferase (Gt) (EC 2.4.1.17) are to be investigated: 1) the Gt-deficient Gunn rat, which is the animal model of the Crigler-Najjar syndrome of humans; 2) the Gt inhibitor associated with breast-feeding jaundice; and 3) the identification of Gilbert's syndrome as a cause of neonatal hyperbilirubinemia. By appropriate chromatographic and electrophoretic protein isolation techniques, the "apparently" defective Gt enzyme protein in Gunn rats is to be isolated to discover if its fundamental peptide composition is deficient. The microsomal microenvironment of the Gt protein is also to be studied to determine whether the Gt deficiency is secondary to the matrix structure in which the Gt enzyme protein is located. The inhibitory substance(s) believed responsible for breast-feeding jaundice of infants in the first few months of life is to be isolated by protein-stripping techniques from serum of mothers whose infants have the disorder and its identity established by GLC-mass spectrographic technology. Such identification will allow preventive measures to be intelligently guided. Although Gilbert's syndrome has been considered a benign disorder of bilirubin clearance of post-pubertal adults, its phenotypic expression in neonatal life may account for the considerable morbidity of neonatal hyperbilirubinemia in otherwise healthy term infants. The parents of infants suspected of having Gilbert's syndrome are to be investigated for the gene(s) presence in them. The response of their serum bilirubin concentrations to fasting and the percentage of bile pigment represented as bilirubin monoglucuronide are to be measured. One or both of these tests will permit the detection of the gene(s) of Gilbert's syndrome in the parents.
NIH ExPorter
NIH ExPorter