PI: Andrew Duncan
Title: Mechanisms of Liver Regeneration Induced by Acetaminophen Toxicity
Description: Liver disorders affect 30 million people in the United States and are the country’s 10th leading cause of death. To improve liver disease treatments, a better understanding of hepatocyte biology is required. The liver contains diploid and polyploid hepatocytes, with polyploids comprising nearly 50% adult human and 90% adult mouse hepatocytes. The functional differences between diploid and polyploid hepatocytes are poorly understood. We previously demonstrated that diploid hepatocytes facilitate rapid liver regeneration, but it remains unknown how diploid and polyploid hepatocytes respond to drug-induced injury. Acetaminophen (APAP) is a common analgesic that can cause acute liver injury, resulting in liver failure and death when taken in excess. When APAP overdose causes extensive centrilobular hepatocyte death, the liver undergoes compensatory proliferation and recovers if the ratio of necrosis to regeneration is low. To investigate the role diploid and polyploid hepatocytes in vivo, we utilize E2f7 and E2f8 liver-specific knockout mice (LKO) where E2f7 and E2f8 are deleted during postnatal development; these mice are functionally normal through 6-9 months of age but are depleted of polyploid hepatocytes (LKO livers are >70% diploid). Preliminary studies indicate that LKO mice enriched with diploid hepatocytes are less damaged and recover faster from APAP injury than wild-type (WT) mice enriched with polyploid hepatocytes. The Grantee shall investigate mechanisms of liver injury and regeneration during APAP-induced liver injury and failure. This project shall determine ploidy-dependent and ploidy-independent mechanisms of liver repair and regeneration following APAP overdose.
Source: Commonwealth of Pennsylvania
Term: 7/1/2021-6/30/22
Amount: $77,260