DEVELOPMENT OF HEPATIC EXCRETORY FUNCTION

本提案的重点是研究的发育成熟

The focus of this proposal is to examine the developmental maturation of the hepatic excretory system for bilirubin and bile salts. Accumulation or deficient excretion of these substances due to immaturity of the hepatic excretory function is associated with hyperbilirubinemia and cholestasis particularly in the premature infants. Studies will be conducted with freshly isolated hepatocytes from fetal and neonatal rabbit up to 60 days of age as the experimental model and will examine the functions of both transport (uptake and secretion) and conjugation in the development of hepatic excretory function. The use of kinetic evaluation and rate constants will provide understanding of the maturational development in terms of number of receptor sites, maximal velocity of uptake, ability of the hepatocytes to concentrate the ligand metabolism and rate of efflux of the ligand (biliary secretion). These studies should thus provide an indication of the limiting factor(s) in hepatic excretatory function for bilirubin and bile acids at various developmental ages. The role of factors associated with hepatic excretory function including albumin binding, ligandin, and bile acids on maturation of hepatic excretion will also be examined. Further studies will be conducted to examine possible mechanisms of neonatal cholestasis. Bile acid transport and metabolism will be characterized and sensitivity of the system to toxic bile acids defined. Maturation of the conjugating enzyme activity in the liver and factors which may enhance it's cellular activity in the premature and newborn will also be examined. It is hypothesized that the limiting factors in hepatic excretion for bilirubin and bile acids will change during development form the premature to late neonate. Understanding of the limiting factor(s) at each of the various ages during development will provide a much better rationale for possible drug intervention in treatment of neonatal jaundice and neonatal cholestasis. The results from thess studies will contribute significantly to understanding the maturation of the hepatic excretory system and may provide ne approaches to treatment of diseases associated with altered or deficient heatic excretion.