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FIBROBLAST GROWTH FACTORS AND NOTCH SIGNALING IN A
DIETHOXYCARBONYL DIHYDROCOLLIDINE-INDUCED HEPATIC
PROGENITOR CELL LIVER INJURY MODEL
by
Christopher Lee Vendryes
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2010
Copyright 2010 Christopher Lee Vendryes
Object Description
| Title | Fibroblast growth factors and notch signaling in a diethoxycarbonyl dihydrocollidine-induced hepatic progenitor cell liver injury model |
| Author | Vendryes, Christopher Lee |
| Author email | Vendryes@USC.edu; cvendryes@chla.usc.edu |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-12-08 |
| Advisor (committee chair) | Tokes, Zoltan A. |
| Advisor (committee member) |
Kalra, Vijay Wang, Kasper |
| Abstract | INTRODUCTION: The liver is a multi-purposeful organ, susceptible to injury. Following acute injury, cells such as hepatocytes, regenerate, while latent hepatic progenitor cell (HPC) become active after chronic liver injury. Some studies suggest Fibroblast growth factors (FGF) may activate HPCs similarly to embryonic liver stem cells. In addition, Notch signaling is critical in bile duct development and injury. With progenitor cell transplantation as an alternative to tissue transplantation, we hypothesize that FGF and Notch signaling pathways induce proliferation of HPC after chronic liver injury.; MATERIALS AND METHODS: Wild-type mice were fed either regular or 0.1% 3,5-diethoxycarbonyl dihydrocollidine (DDC) chow to induce injury. Transgenic, dominant-negative RosartTA;tet(o)sFGFR2b+/- mice were given doxycycline 2 days prior and throughout DDC injury. mRNA and immunostaining of FGF and Notch receptors and ligands were performed. Cells isolated from transgenic mice were fluoresecently sorted for stem cell marker CD49f. In addition, western blot analyses of downstream targets were studied.; RESULTS: After confirming DDC injury, FGF signaling was identified, with expression of Fgf1, 10, and receptor Fgfr1b and c. Similarly, FGFR1, proliferating cell nuclear antigen (PCNA), Notch-1, delta like ligand 1, and Notch-1 intracellular domain (NICD), were expressed after DDC injury. With dominant negative transgenic mice, we saw a reduction of CD49fpos cells, FGFR1, phosphorylated-AKT, and Notch downstream mediator Hes-1 between induced and control groups.; DISCUSSION: We believe that FGF and Notch signaling are involved in the induction of HPC after chronic liver injury. Expression of FGFR1 suggests that chronic liver injury may work through this receptor. Dominant-negative soluble FGFR2b analysis suggests FGF may have an influence on a HPC population with a reduction in FGFR1, CD49fpos cells, PCNA, and Hes-1. Notch-1 expression after chronic injury may associate with prior data describing Notch-2 as a marker for bile duct disease. |
| Keyword | fibroblast growth factors; cirrhosis; notch; liver |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3590 |
| Rights | Vendryes, Christopher Lee |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Vendryes-4226 |
| Archival file | uscthesesreloadpub_Volume14/etd-Vendryes-4226.pdf |
Description
| Title | Page 1 |
| Full text | FIBROBLAST GROWTH FACTORS AND NOTCH SIGNALING IN A DIETHOXYCARBONYL DIHYDROCOLLIDINE-INDUCED HEPATIC PROGENITOR CELL LIVER INJURY MODEL by Christopher Lee Vendryes A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (BIOCHEMISTRY AND MOLECULAR BIOLOGY) December 2010 Copyright 2010 Christopher Lee Vendryes |
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