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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Thomas E. Starzl, MD Postdoctoral Research Fellowship
University of Pittsburgh
Project Title: Elucidating role and regulation of β-catenin and NF-κB interactions in liver biology
The purpose of Dr. Nejak-Bowen’s research project is to better understand the processes by which the liver survives and repairs itself after insult or injury. Fulminant hepatic failure (FHF) is a rare disorder that occurs when the liver sustains severe damage, and can be caused by a variety of agents, such as viruses and toxins. FHF is associated with high mortality in the absence of liver transplantation. Understanding the signaling pathways involved in liver regeneration (LR) is important for identifying new therapies for treating liver injury, and stimulating this process during FHF could potentially offer a therapeutic alternative to transplantation. Because β-catenin and NF-κB share redundant biological effects during LR, Dr. Nejak-Bowen hypothesizes that β-catenin interacts with NF-κB to enhance cell proliferation via transactivation of cyclin-D1 gene expression, whereas the absence of β-catenin permits NF-κB to regulate cell survival via distinct target gene expression. Through balanced in vitro and in vivo approaches, she proposes to test this hypothesis by characterizing the association of NF-κB/β-catenin during proliferation. In the first aim, hepatoma cell lines will be treated with various ligands & growth factors to stimulate either the β-catenin or NF-κB pathways, or both, as assessed by luciferase reporter activity. Once these systems have been established, she will then remove various components of the NF-κB & β-catenin pathways through the use of silencing RNA in order to study the impact on cyclin-D1 reporter activity, cell survival, and proliferation. Dr. Nejak-Bowen expects that in the presence of ligands, inhibiting both β-catenin and NF-κB individually should decrease cyclin-D1 reporter activity, β-catenin siRNA should decrease proliferation while increasing cell survival, and NF-κB siRNA should decrease both proliferation and survival. In the second aim, she will characterize the association and expression of NF-κB and β-catenin after LR by immunoprecipitation and colocalization studies that should demonstrate the interaction of these two proteins in the nucleus within hours after partial hepatectomy (PH). Additionally, she will determine whether both NF-κB and β-catenin are necessary for proliferation during LR by interbreeding NF-κB lacZ transgenic (TG) mice with β-catenin conditional knockout (KO) mice & examining the expression of β-galactosidase activity at various times after PH. Dr. Nejak-Bowen predicts that lack of β-catenin will prevent the synergistic activation of proliferation, which will be manifested by delayed or absent NF-κB activity in the early hours after PH. Thus, β-catenin may be an important component of balancing the context-dependent pro-proliferation versus pro-survival functions of NF-κB, & could be an attractive target for clinical therapies that enhance cell survival and/or proliferation in liver injury.
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