DEVELOPMENT OF HEPATIC EXCRETORY FUNCTION

这项建议的重点是检查儿童的发育成熟度 肝脏排泄系统中的胆红素和胆盐。累积或 由于肝脏不成熟而导致这些物质的排泄不足 排泄功能与高胆红素血症和胆汁淤积有关 尤其是早产儿。研究将在以下情况下进行 新鲜分离的胎兔和新生兔肝细胞至60d 作为实验模型，并将检查两者的功能 发育过程中的转运(摄取和分泌)和结合作用 肝脏排泄功能。动力学评价法和速率法的应用 常量将提供对 根据受体位置的数量，最大摄取速度，能力 肝细胞浓缩配体代谢和外流速率 配体(胆汁分泌物)。因此，这些研究应该提供一个 限制因子(S)在肝排泄功能中的适应证 不同发育年龄的胆红素和胆汁酸。的作用 与肝脏排泄功能相关的因素，包括白蛋白 结合、配基和胆汁酸对肝排泄成熟的影响 也要接受检查。我们会进行进一步研究，以研究是否有可能 新生儿胆汁淤积的机制。胆汁酸的转运和代谢 将表征和系统对有毒胆汁酸的敏感性 已定义。肝脏和肝脏中结合酶活性的成熟 可能增强早产儿和早产儿细胞活性的因素 新生儿也将接受检查。据推测，限制 影响肝脏排泄胆红素和胆汁酸的因素将发生变化 在发育过程中，从早产儿到晚期新生儿。了解 发育过程中各个年龄段的限制因素(S)将 为治疗中可能的药物干预提供了更好的理由 新生儿黄疸和新生儿胆汁淤积症。来自Thess的结果 研究将有助于理解人的成熟度 肝排泄系统，并可能提供新的治疗方法 与热排泄改变或不足有关的疾病。

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.