Long-term objectives of this proposal are to elucidate the molecular mechanisms responsible for the therapeutic effects of phototherapy of neonatal jaundice; to improve the effectiveness and safety of phototherapy; and to define, at the molecular level, structural features that control the transport and metabolism of bilirubin and related compounds by the liver.
Specific aims are: 1. To characterize the molecular structures and properties of phototherapy intermediates and identify factors that influence their formation and excretion kinetics in vivo. 2. To determine why the excretion of phototherapy intermediates is less efficient in human patients than in the jaundiced. rat animal model. 3. To locate the tissue site(s) where the most important photochemical reactions of phototherapy occur. 4. To define the importance of molecular shape, lipophilicity, and hydrogen bonding in the transhepatic transport and intracellular partitioning of bilirubin and related compounds. 5. To characterize the topography and molecular recognition targets of bilirubin glucuronyl transferase. 6. To investigate the effects of volatile general anesthetics on the structure of albumin-bound bilirubin. 7. To measure the chiroptical properties of bilirubin glucuronides and develop methods for their synthesis.
These aims will be achieved by measuring the physicochemical properties of bilirubin and related compounds in vitro; by investigating the effects of light on jaundiced rats; and by studying the transport and metabolism of phototherapy intermediates and bilirubin model compounds in normal rats, in mutant rats with congenital defects in bilirubin metabolism, and in isolated perfused liver preparations from these animals. The project is directly related to the prevention of bilirubin-induced brain damage in infants and in patients with the Crigler-Najjar syndrome, to the diagnosis and understanding of hepatobiliary disease, to the therapeutic and biological effects of light on humans, and to the physiologic effects and mechanism of general anesthetics. The work will lead to safer and more effective methods for the treatment of familial hyperbilirubinemia and jaundice in the newborn.
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