This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. At present, liver transplantation is the only available treatment for patients with liver failure. Alternative therapies such as hepatocyte transplantation have been sought. Research to date has focused on the identification and isolation of various populations of hepatic cells capable of liver repopulation. These studies have shown that a subpopulation of hepatic epithelial cells derived from the mid-gestation fetal rat are capable of engrafting, proliferating, and differentiating into functional hepatocytes upon transplantation to injured and normal adult rat liver. More recently, oval cells which are activated during liver injury have been shown to differentiate into hepatocytes and cholangiocytes upon transplantation. Although the isolation and engraftment capacity of these cells has been well characterized, the mechanisms controlling their proliferation, growth, and differentiation have not been studied. Based on previous work in our laboratory on liver development in the rat, we hypothesize that oval cells and the subpopulation of fetal cells capable of liver repopulation will exhibit a selective growth advantage, the hallmarks of which will be mitogen-independence, sustained c-Myc activity, and rapamycin resistance. We will address this hypothesis by studying the regulation of key mitogenic pathways involving ERK, phosphatidylinositol 3-kinase (PI3K), Akt and mTOR, JNK and Wnt/b-catenin in these cell types. We will also study the regulation of the c-Myc/Max/Mad network. Western immunoblotting, immunofluoresence, RT-PCR, and chromatin immunoprecipitation will be used to delineate the role of these signaling networks in oval cell and fetal liver progenitor proliferation and growth. The proposed studies may lead to the identification of factors that promote or inhibit liver progenitor cell engraftment and expansion. Furthermore, given the role of oval and liver progenitor cells in hepatic cancer, these studies may provide insight into mechanimsms of hepatic carcinogenesis
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