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DEVELOPMENT OF HEPATIC EXCRETORY FUNCTION

肝脏排泄功能的发育

基本信息

批准号：
3152148
负责人：
MICHAEL A EVANS
金额：
$ 5.94万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-04-01 至 1986-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3152148
关键词：
bile circulation biliary tract disorder bilirubin embryo /fetus excretion gestational age growth /development liver cells liver function mathematical model neonatal transient jaundice newborn animals perfusion premature infant animal steroid metabolism

项目摘要

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.

这项建议的重点是审查发展成熟的胆红素和胆汁盐的肝排泄系统。积累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。研究将与从胎兔和新生兔新鲜分离的肝细胞（长达60天）年龄作为实验模型，并将检查两者的功能运输（吸收和分泌）和接合在发展中的作用肝脏排泄功能动力学评价和速率的使用常数将提供了解的成熟发展，根据受体位点的数量，最大摄取速度，肝细胞浓缩配体代谢和流出率胆汁分泌（biliary secretion）因此，这些研究应该提供一个肝排泄功能限制因素的指示胆红素和胆汁酸在不同发育年龄。的作用与肝排泄功能相关的因素，包括白蛋白结合、配体素和胆汁酸对肝排泄成熟的影响将也要检查。将进行进一步的研究，新生儿胆汁淤积的机制。胆汁酸转运和代谢将表征系统对毒性胆汁酸的敏感性定义了肝脏中结合酶活性的成熟，这些因素可能会增强早产儿和早产儿的细胞活性，新生儿也将接受检查。据推测，胆红素和胆汁酸的肝排泄因子将改变在从早产儿到晚期新生儿的发育过程中。了解发育过程中各个年龄段的限制因素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。结果从thess 这些研究将有助于了解肝排泄系统，并可能提供新的方法来治疗与排泄改变或排泄不足有关的疾病。