Liver regeneration following partial hepatectomy provides one of the few examples of a physiologic growth response occurring in the intact animal. This application is directed to understanding the basic molecular mechanisms that: 1) trigger regeneration, and 2) allow the liver to concurrently grow and maintain differentiated function.
Specific aim 1 : Among the earliest responses observed in the regenerating liver are the activation of PHF/NF-Kappa B and Stat3, transcription factors that are normally induced by cytokines such as TNF alpha and IL-6. The PI is examining the importance of PHF/NF-Kappa B by analyzing the regenerative capacity of mouse livers from animals that are genetically missing the p50 subunit of PHF/NF-Kappa B. Similarly, she is assessing the impact of Stat3 by analyzing IL-6 negative animals that do not induce Stat3 after partial hepatectomy. Preliminary studies indicate that regeneration is abnormal in IL-6-/- animals. She will also assess the impact of C/EBP beta deficiency on liver regeneration. It is shown that there is a relative increase in C/EBP beta to alpha levels during regeneration which may be important for progression through the cell cycle and maintenance of the liver phenotype during regeneration. In this way, she will be able to determine the subset of immediate-early genes that are specific targets of PHF/NF-Kappa B, Stat 3, and C/EBP beta. By measuring the impact of these mutations on the regenerative capacity, and assessing the potential interplay between the PHF/NF-Kappa B, Stat3, and C/EBP beta pathways, the PI will determine the role of specific cytokine/growth factor pathways in triggering liver regeneration.
Specific aim 2 : To identify additional """"""""liver regeneration factors"""""""", she will determine what promoter elements are responsible for induction of the liver-enriched immediate-early gene PRL-1 during liver regeneration. PRL-1 immediate-early and late expression is normal in the knockout mice examined so far. These studies will allow the definition of novel factors and pathways that control regeneration.
Specific aim 3 : As proteins encoded by some immediate-early and delayed-early genes are the ultimate regulators of liver regeneration, she will trace the transcriptional cascade that ultimately leads to liver cell growth. She will study the regulation of specific target genes of IL-6/Stat3, NF-Kappa B and C/EBP beta. They have already identified a specific subset of immediate-early genes including AP1 factors (jun, fos, LRF-1) and c-myc that are expressed at abnormally low levels in IL-6-/- mice. She will study their regulation in more detail and assess the role of Stat3 in their regulation. During regeneration, the liver must maintain vital functions including metabolic homeostasis despite the acute loss of two thirds of its mass. This is accomplished as a result of the induction of liver-specific immediate-early genes such as glucose-6 phosphatase (G6Pase) and PEPCK. The G6Pase gene is not induced appropriately in p50/NF-Kappa B1 -/-mice. She hypothesizes that this is because G6Pase mRNA is normally regulated by synergistic interactions between PHF/NF-Kappa B and endogenous constitutive factors such as C/EBP which continue to be expressed during liver regeneration. In addition to animal studies, she will design studies to test this hypothesis by examining direct effects and the interplay of C/EBPs and NF-Kappa B on the G6Pase gene in cell culture systems in which the local environment can be carefully regulated.
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