PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy

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PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy

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dc.contributor.advisor B. Mark Evers, M.D. en_US
dc.creator Lindsey Nicole Jackson en_US
dc.date.accessioned 2011-12-20T16:05:45Z
dc.date.available 2010-09-28 en_US
dc.date.available 2011-12-20T16:05:45Z
dc.date.created 2008-12-18 en_US
dc.date.issued 2008-11-25 en_US
dc.identifier.other etd-12182008-133713 en_US
dc.identifier.uri http://hdl.handle.net/2152.3/297
dc.description.abstract Hepatic resection is associated with rapid proliferation and regeneration of the remnant liver. Phosphatidylinositol 3-kinase (PI3K), composed of a p85Ą regulatory and a p110Ą catalytic subunit, participates in multiple cellular processes, including cell growth and survival; however, the role of PI3K in liver regeneration has not been clearly delineated. In these studies, I used the potent PI3K inhibitor, wortmannin, and small-interfering RNA (siRNA) targeting the p85Ą and p110Ą subunits to determine if total or selective PI3K inhibition would abrogate the proliferative response of the liver following resection. After partial hepatectomy in mice, there is an increase in PI3K activity; total PI3K blockade with wortmannin, and selective inhibition of p85Ą or p110Ą with siRNA resulted in a significant decrease in hepatocyte proliferation, especially at the earliest timepoints (ie, 48h and 72h). Fewer macrophages and Kupffer cells were present in the regenerating liver of mice treated with wortmannin or siRNA to p85Ą or p110Ą, as reflected by a paucity of F4/80+ cells present by immunohistochemistry (IHC). Additionally, PI3K inhibition led to an aberrant hepatocyte architecture characterized by vacuolization, lipid deposition, and glycogen accumulation. My data demonstrate that PI3K/Akt pathway activation plays a critical role in the early regenerative response of the liver after resection; inhibition of this pathway markedly abrogates the normal hepatic regenerative response, perhaps by inhibiting macrophage infiltration and cytokine elaboration and thus hepatocyte priming for replication. en_US
dc.format.medium electronic en_US
dc.language.iso eng en_US
dc.rights Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works. en_US
dc.subject wortmannin en_US
dc.subject phosphatidylinositol 3-kinase en_US
dc.subject p85-alpha en_US
dc.subject p110-alpha en_US
dc.subject liver regeneration en_US
dc.title PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy en_US
dc.type.material text en_US
dc.type.genre dissertation en_US
thesis.degree.name PhD en_US
thesis.degree.level Doctoral en_US
thesis.degree.grantor The University of Texas Medical Branch en_US
thesis.degree.department Cell Biology en_US
dc.contributor.committeeMember Sundararajah Thevananther, Ph.D. en_US
dc.contributor.committeeMember Kathleen O'Connor, Ph.D. en_US
dc.contributor.committeeMember Frank C. Schmalstieg, M.D., Ph.D. en_US
dc.contributor.committeeMember Cornelis Elferink, Ph.D. en_US

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