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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
American Association for the Study of Liver Diseases/American Liver Foundation Liver Scholar Award
University of Pennsylvania
Project Title: The role of Keap1/Nrf2 in modulating redox status of hepatic progenitor cells
Background: Although increased oxidative stress creates a significant challenge in cell transplantation therapy, the role of the Keap1/Nrf2 pathway in HPCs has not been investigated thoroughly. Dr. Shin’s laboratory recently established protocols for isolating and expanding Foxl1-expressing HPCs in culture. Her preliminary data indicates that activation of Nrf2 signaling by downregulating Keap1 expression protects HPCs from oxidative stress. This led to her hypothesis that the Keap1/Nrf2 signaling pathway plays a critical role in protecting HPCs from oxidative stress.
Approaches: Dr. Shin’s first aim is to determine the effects of redox status on survival of HPCs. Foxl1-Cre; RosaYFP/YFP mice will be treated with the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to activate proliferation of HPCs and to increase oxidative stress in the liver. Levels of reactive oxygen species (ROS), oxidized DNA, oxidized proteins, and GSH/GSSG ratio will be analyzed in primary HPCs. The long-term goal of the project is to evaluate the therapeutic potential of genetically modified HPCs. The second aim of this project is to determine the role of Keap1/Nrf2 in redox status as well as the survival of endogenous HPCs and their descendants. To activate Nrf2 signaling in Foxl1-expressing HPCs, she will delete Keap1 in HPCs by crossing Foxl1-Cre; RosaYFP/YFP mice to Keap1L/L mice. Aim 3 is to compare the engraftment efficiency of the HPCs isolated from control and Keap1-knockout mice following transplantation into Fah-/- recipient mice. Additionally, Nrf2 activators will be tested for their ability to enhance survival of transplanted HPCs.
Anticipated results: Dr. Shin predicts that oxidative stress in the liver following injury challenges HPCs and that this increased oxidative stress inhibits survival of HPCs and their descendants. She anticipates that activation of Keap1/Nrf2 signaling will decrease oxidative stress and enhance survival of endogenous HPCs and their descendants. Additionally, Dr. Shin predicts that activation of Nrf2 using genetic and pharmacological approaches will enhance engraftment or survival of HPCs transplanted into recipient mice. The experiments proposed in this application will be the first to investigate the role of redox balance and Keap1/Nrf2 signaling in HPCs. Furthermore, this approach will overcome one of the major challenges of cell transplantation therapy: transient survival of transplanted cells in the recipient liver.