? Liver regeneration is a unique biological response in which normally quiescent, differentiated hepatocytes regain proliferative activity. Although the process involves the partially synchronized replication of more than 95% of hepatocytes, replication is strictly regulated and ceases when the liver regains its original mass. Understanding the mechanisms that initiate and regulate liver regeneration is of great scientific and clinical importance. In years 30 to 32 of this MERIT award we have demonstrated that Tumor Necrosis Factor (TNF) one of the main cytokines involved in the initiation of liver regeneration acts both through the NFKBIIL-GISTAT3 pathway that we have previously described, and by transactivating the EGF receptor (EGFR). Transactivation of EGFR involved the release of EGF ligands anchored into the cell membrane by the metalloproteinase TACE, triggering a mitogenic cascade involving ERK1/2 and PKB. We have also shown that one of these ligands, HB-EGF, whose expression is regulated by c-junlAP1 complexes, plays a key role in linking hepatocyte priming at the start of liver regeneration with cell cycle progression occurring many hours later. This application for extension of the MERIT project period is based on these findings and on other work demonstrating the role of NFKB and SOCS family genes in the initiation of liver regeneration. Placing emphasis on appropriate mouse models. and results from ongoing work, we designed experiments which address key issues regarding the mechanisms of liver regeneration:? 1) the control of hepatocyte survival and proliferation by GSH, 2) LPS receptor signaling as a triggering mechanism for liver regeneration,3) the role of SOCS-3 in preventing cytokine toxicity in the regenerating liver,4) the mechanisms by which c-junlAP-1 complexes control HB-EGF induction and 5) the role of cytokines in regulating differential hepatocyte and progenitor cell. The research plan for the extension of this MERIT award consists of 5 aims:? 1) Determine whether glutathione (GSH) and reactive oxygen species (ROS) production regulate growth and survival responses in the regenerating liver using Glutamate-LCysteine Ligase Modifier subunit knockout mouse (GCLM KO mice) as a model.? 2) Determine whether LPS signaling initiates liver regeneration by analysis of liver regeneration in MyD88, TLR4, TLR2 and CD14 KO mice.? 3) Investigate whether the lack of feedback regulation of the IL-GISTAT3 pathway in liver specific SOCS-3 KO mice prevents liver regeneration and triggers the acute phase response.? 4) Investigate the mechanism of induction of HB-EGF in the regenerating liver by cjunIAP-1 complexes, as a linkage between priming and cell cycle progression during liver regeneration.? 5) Determine whether IFNy in combination with TNF can change liver regeneration after PH from a hepatocyte to a liver precursor cell (oval cell) response.?
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