Biology of the liver is regulated by a complex network of many signal transduction pathways. Theunderstanding of molecular basis of biological processes in the liver is highly significant for the support ofhealthy life in humans. This renewal of R01 application investigates molecular mechanisms of liver growthand differentiation, liver regeneration after surgical resections and liver recovery after chemical injuries. Twomembers of C/EBP family, C/EBPa and C/EBPb, are critical regulators of liver biology and liver functions. Inthe course of previous studies, we found that phosphorylation of C/EBPa at S193 increases its hetero-dimerization with C/EBPb and subsequent interactions of the C/EBPa/b dimers with chromatin remodelingproteins p300 and HDAC1. While C/EBP-p300 complexes activate promoters of target genes, C/EBP-HDAC1complexes mainly repress the promoters. Therefore, amounts of C/EBPa/b-p300 and C/EBPa/b-HDAC1complexes are changed during distinct biological processes in appropriate ratios. The main hypothesis ofthis application is that the network of C/EBP proteins and chromatin remodeling proteins regulatespost-natal liver growth and differentiation, liver regeneration after surgical resections and liver injuryafter CCl4 treatments. We generated 4 genetically modified mouse models: C/EBPa-S193D mice (phosphor-mimicking mutation), C/EBPa-S193A mice (no phosphorylation on S193), transgenic mice which expressdominant negative p300 (dnp300) and double knockin-transgenic S193D-dnp300 mice. We found thatC/EBPa-S193A mutant does not interact with HDAC1; however, S193D mutation increases interactions ofC/EBPa with HDAC1. Our data show that proliferation of the liver is inhibited in S193D mice, while liverproliferation is increased in S193A mice.
Specific Aim 1 will test the hypothesis that a balance of C/EBPa/b-p300 and C/EBPa/b-HDAC1 complexes is required for normal post-natal liver development.
Specific Aim 2 will test the hypothesis that C/EBPa controls entry of hepatocytes into cell cycle and termination of liverregeneration after partial hepatectomy (PH) through interactions with HDAC1.
Specific Aim 3 will examine thehypothesis that severe liver injury in young S193D and old WT mice after treatments with CCl4 is caused byC/EBPa/b-HDAC1-mediated repression of telomere reverse transcriptase, TERT.
This aim i s based on theobservations that a) CCl4 causes severe liver damage and increased apoptosis in young S193D and old WTmice (both have high levels of C/EBPa-HDAC1 complexes); b) that basal levels of TERT are reduced inyoung S193D mice and in old WT mice; and c) that the TERT promoter contains binding sites for C/EBPproteins. In summary, the elucidation of the mechanisms of liver proliferation during post-natal developmentand after surgical resections as well as mechanisms of liver recovery after drug-mediated injury will have highimpact on the field of liver biology and will provide a step for the further studies in clinical settings.

Public Health Relevance

The application examines the mechanisms of liver growth and differentiation after birth and liver regenerationafter surgical resections and after injury. The elucidation of these mechanisms is required to developapproaches to improve liver functions after surgical resections and after liver injury.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Gaillard, Shawn R
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Cincinnati Children's Hospital Medical Center
United States
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