MODULATION OF REGENERATION IN ALCOHOLIC LIVER DISEASE

酒精滥用，无论如何定义，都是一个主要的健康问题 西方社会。在美国，酗酒已成为第四大 成人最常见的死因。并不是所有酗酒的人 出现肝脏损伤(估计在10%到31%之间)；然而， 肝硬变的标准死亡率(95%死于酒精性肝 疾病)大于90/100,000的专业人员和技术人员 工人们。饮酒量稳定的人患肝硬变的风险比 间歇性饮酒者；这表明间歇性摄入 让肝脏有时间进行修复。在任何情况下，再生的 肝脏的功能对其从酒精诱导的恢复至关重要 疾病。这项拟议中的研究将调查分子 正常和酒精损伤肝脏的调控机制 再生。 在正常的哺乳动物肝脏中几乎不存在细胞分裂。 然而，在化学、病毒或物理损害之后，肝脏 通过启动DNA合成和有丝分裂来做出反应，从而导致 器官肿块的恢复。此响应是同步的，并且 被认为是由DNA合成调节器控制的。这 已知再生过程在体内和体内都是有缺陷的 乙醇注射后的体外实验。尽管有密集的 控制细胞增殖的分子机制研究进展 肝脏的动态平衡仍不清楚。最近我们有 开发了一种生物检测方法来检测编码 用于DNA合成的调节剂。我们利用了这一点 微注射技术鉴定两种细胞中的抑制组分 静息状态下的大鼠肝脏mRNA及其再生刺激组分 大鼠肝组织中的mRNA。大鼠静息肝组织中编码哪些基因的mRNA 用于抑制的基因已被丰富，并已构建了 已生成。本文提出的方案是分离cdna克隆。 对DNA的抑制剂和刺激物具有互补性 在大鼠肝脏转录的合成。对抑制物(S)的研究可能 对失联以来肝癌发展的洞察 一种DNA合成抑制剂可能会导致永生。 刺激因子在正常人群中表达的研究 再生将提供一个比较标准，应该是 帮助确定参与的乙醇敏感途径 肝脏再生有缺陷。此外，了解 面向未来再生点的启动机制 酒精性肝损伤的原位再生治疗 组织。

Alcohol abuse, however defined, is a major health problem for Western societies. In the U.S., alcoholism has become the fourth most common cause of death in adults. Not all who abuse alcohol develop liver damage (estimates range from 10 to 31%); however, the standard mortality for cirrhosis (95% due to alcoholic liver disease) is greater than 90/100,000 for professional and technical workers. Steady drinkers are more at risk for cirrhosis than are intermittent drinkers; this suggests that intermitent ingestion allows the liver time for repair. In any case, the regenerative ability of the liver is crucial to its recovery from alcohol-induced disease. The proposed research will investigate the molecular mechanisms controlling normal and alcohol-damaged liver regeneration. Cell division is virtually nonexistent in normal mammalian liver. However, following chemical, viral or physical damage, the liver responds by initiating DNA synthesis and mitosis, which results in restoration of organ mass. This response is synchronous and is thought to be controlled by modulators of DNA synthesis. This regenerative process is known to be defective both in vivo and in vitro after administration of ethanol. In spite of intensive investigation, the molecular mechanisms controlling proliferative homeostasis in the liver remain unknown. Recently we have developed a biological assay to detect mRNA species which code for modulators of DNA synthesis. We have employed this microinjection technique to identify both an inhibitory fraction in resting rat liver mRNA and stimulatory fractions in regenerating rat liver mRNA. mRNA species from resting rat liver which code for inhibition have been enriched and a cDNA library has been generated. The project proposed here is to isolate cDNA clones complementary to both inhibitors and stimulators of DNA synthesis transcribed in rat liver. Study of the inhibitor(s) may give insights into the development of hepatocarcinoma since loss of a DNA synthesis inhibitor might lead to immortalization. Study of the expression of the stimulators during normal regeneration will provide a comparative standard which should help in identifying the ethanol-sensitive pathways involved in defective liver regeneration. Further, knowledge of the mechanisms for initiation of regeneration point toward future therapies based on in situ regeneration of alcohol-damaged liver tissue.