MODULATION OF REGENERATION IN ALCOHOLIC LIVER DISEASE

酗酒，无论如何定义，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 成人最常见的死亡原因。 不是所有酗酒的人 出现肝损伤（估计范围为10 - 31%）;然而， 肝硬化的标准死亡率（95%归因于酒精性肝 疾病）大于90/100，000的专业和技术 工人 稳定饮酒者比正常人更容易患肝硬化。 间歇性饮酒者;这表明间歇性摄入 让肝脏有时间修复 在任何情况下，再生 肝脏的能力是至关重要的，它从酒精诱导的恢复。 疾病 拟议的研究将调查分子 控制正常和酒精损伤肝脏的机制 再生 在正常哺乳动物肝脏中几乎不存在细胞分裂。 然而，在化学、病毒或物理损伤后，肝脏 通过启动DNA合成和有丝分裂， 器官质量的恢复。 这种反应是同步的， 被认为是由DNA合成的调节剂控制的。 这 已知再生过程在体内和体内都是有缺陷的。 乙醇给药后体外。 尽管密集 研究，控制增殖的分子机制， 肝脏内的稳态仍然未知。 最近我们 开发了一种生物测定法来检测编码 DNA合成的调节剂。 我们利用这个 显微注射技术，以确定两个抑制级分， 静息大鼠肝mRNA和再生刺激组分 大鼠肝脏mRNA。 来自静息大鼠肝脏的mRNA种类， 已经富集了用于抑制的cDNA文库， 生成的. 本文提出的项目是分离cDNA克隆， 与DNA的抑制剂和刺激剂互补 在大鼠肝脏中转录的合成。 抑制剂的研究可 肝癌的发展，因为损失的见解 DNA合成抑制剂可能会导致永生 正常人肝组织中刺激因子表达的研究 再生将提供一个比较标准， 有助于确定乙醇敏感的途径， 肝脏再生缺陷 此外，知识的 再生启动机制指向未来 基于酒精损伤肝脏原位再生的疗法 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.