METABOLIC HOMEOSTASIS IN LIVER REGENERATION

肝部分切除后的肝再生是为数不多的模型之一。 在该实验室中，可以研究完整的 动物。再生是从中毒中恢复的重要组成部分， 对肝脏的代谢和免疫损伤，并在以下方面很重要 肝脏移植。尽管失去了三分之二的肝脏质量， 新陈代谢和合成动态平衡得以维持。葡萄糖动态平衡是 肝脏特异性即刻早期基因的诱导 包括那些编码葡萄糖异生酶的酶，如葡萄糖-6- 磷酸酶和PEPCK。这种诱导肝脏再生的基础 然而，人们并不清楚，这很可能涉及到参与 生长诱导转录因子，包括核因子-kappaB和STAT3。我们 假设这些因素通过合作发挥作用 与构成的肝脏特异性转录因子的相互作用。 C/EBP蛋白，在肝再生和肝再生过程中表达 其他肝脏因子如hnf-L是合理的候选转录因子。 这类复杂监管的因素。很可能C/EBPalpha 对于调节即刻早期基因是很重要的 包括葡萄糖-6-磷酸酶和PEPCK在内的葡萄糖稳态 C/EBPalpha缺陷小鼠在出生时就会出现严重的低血糖，而且不会 证明了这些mRNA的正常诱导。我们将研究 基因激活的基础，这些基因对维持人类免疫功能非常重要 使用两种方法实现代谢动态平衡。(L)潜在的靶基因 在再生过程中被C/EBPalpha激活的将被识别 在C/EBPalpha缺陷杂合子小鼠中，我们假设会 C/EBPalpha调控基因表达水平的微妙变化 基因对肝部分切除的反应。在确定了 潜在的C/EBPalpha激活、启动子靶点基因 这些基因的区域将在组织培养系统中进行检测 确定特定的C/EBPalpha启动子元件和调控元件 其他肝脏因子和生长诱导转录因子 有助于这些基因的激活。(2)我们会决定 C/EBP蛋白、HNF-1和生长诱导因子在血管生成中的作用 葡萄糖-6-磷酸酶基因的激活，我们假设它是激活的 在再生过程中被C/EBPalpha。我们将分离并测序 启动子区域，并确定重要的调控元件 在组织培养系统中激活该基因的转录因子。 确定肝脏特异性即刻早期基因激活的基础 对新陈代谢平衡的重要性将增强我们对 肝脏在再生过程中保持其分化状态。 本提案中概述的研究将在 赞助Rebecca Taub博士，她是公认的 肝脏再生领域，其实验室将提供 为候选人的继续培训提供良好的环境和 发展成为肝病领域的独立研究员。

Liver regeneration following partial hepatectomy is one of the few models in which it is possible to study cellular proliferation in the intact animal. Regeneration is an important component of recovery from toxic, metabolic, and immunologic injury to the liver and is important following liver transplantation. Despite the loss of two-thirds of the liver mass, metabolic and synthetic homeostasis is maintained. Glucose homeostasis is mediated by the induction of liver-specific immediate-early genes including those which encode gluconeogenic enzymes such as glucose-6- phosphatase and PEPCK. The basis for this induction in liver regeneration is not well understood, however, it is likely to involve the participation of growth-induced transcription factors including NF-kappaB and Stat3. We hypothesize that these factors exert their effects through cooperative interactions with constitutive liver-specific transcription factors. C/EBP proteins, which are expressed throughout liver regeneration and other hepatic factors such as HNF-l are logical candidate transcription factors for this type of complex regulation. It is likely that C/EBPalpha is important for the regulation of immediate-early genes necessary for glucose homeostasis including glucose-6-phosphatase and PEPCK since C/EBPalpha deficient mice are profoundly hypoglycemic at birth and do not demonstrate the normal induction of these mRNAs. We will examine the basis of activation of genes which are important for the maintenance of metabolic homeostasis using two approaches. (l) Potential target genes which are activated by C/EBPalpha during regeneration will be identified in C/EBPalpha deficient heterozygote mice which we hypothesize will manifest subtle changes in the level of expression of C/EBPalpha regulated genes in response to partial hepatectomy. Following identification of genes which are potential C/EBPalpha targets of activation, promoter regions of these genes will be examined in tissue culture systems to identify specific C/EBPalpha promoter elements and regulatory elements for other hepatic factors and growth-induced transcription factors which contribute to the activation of these genes. (2) We will determine the contribution of C/EBP proteins, HNF-1, and growth-induced factors to the activation of glucose-6-phosphatase a gene which we postulate is activated by C/EBPalpha during regeneration. We will isolate and sequence the promoter region and identify important regulatory elements for transcription factors which activate this gene in tissue culture systems. Defining the basis for activation of liver-specific immediate-early genes important for metabolic homeostasis will enhance our understanding of how the liver maintains its differentiated state during regeneration. The studies outlined in this proposal will be performed under the sponsorship of Dr. Rebecca Taub, who is an acknowledged expert in the field of liver regeneration and whose laboratory will provide an outstanding environment for the candidate's continued training and development as an independent investigator in hepatology.