Albumin-AFP Gene Family Regulation in Fetal and Adult Liver

描述(申请人提供)：哺乳动物的肝脏发育需要以高度有序的方式顺序激活基因。一旦被激活，肝脏中的基因表达水平必须持续对细胞外信号做出反应，才能使生物体保持生理动态平衡。我们一直在研究小鼠甲胎蛋白(AFP)基因作为肝脏特异性基因调控的模型。这些研究主要集中在AFP增强子区域。最近，我们对白蛋白-甲胎蛋白基因家族中所有基因的调控越来越感兴趣。这项建议的一个主要目标是研究AFP增强子在控制肝脏中这一基因家族中的作用。由于AFP在胎肝中被激活，在出生时被关闭，并在肝损伤和肝癌模型中重新激活，这些研究应该有助于阐明肝损伤和肝癌发生过程中发生的转录变化的基础。我们也对研究成人肝脏的带状调节过程感兴趣。带状基因表达是一种机制，允许肝脏中不同亚群的肝细胞进行不同的代谢活动。在受损的肝脏和肿瘤肝细胞中，带状基因调控可能被破坏。由于带状基因调控对于肝脏执行其正常功能是必不可少的，因此了解正常和疾病肝脏中这种调控的基础是很重要的。

DESCRIPTION (provided by applicant): Mammalian liver development requires the sequential activation of genes in a highly ordered manner. Once activated, levels of gene expression in the liver must continually be responsive to extracellular signals in order for organisms to maintain physiological homeostasis. We have been studying the mouse alpha- fetoprotein (AFP) gene as a model of liver-specific gene regulation. These studies have focused on the AFP enhancer region. More recently, we have become increasingly interested regulation of all genes in the albumin-AFP gene family. One main goal of this proposal is to investigate the role of the AFP enhancers in the control of this gene family in the liver. Since AFP is activated in the fetal liver, shut-off at birth, and reactivated in models of liver damage and liver cancer, these studies should help elucidate the basis of transcriptional changes that occur during liver damage and hepatocarcinogenesis. We are also interested in studying the process of zonal regulation in the adult liver. Zonal gene expression is a mechanism that allows different subpopulations of hepatocyte in the liver to carry out distinct metabolic activities. The zonal gene regulation can be disrupted in damaged liver and in neoplastic liver cells. Since zonal gene regulation is essential for the liver to carry out its normal function, it is important to understand the basis for this control in the normal and diseased liver.