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THE RESPONSE OF ALLOGRAFT INFLAMMATORY FACTOR-1 TO
NEUROTOXIC INJURY, AND ITS ROLE AS A SECRETED PROTEIN.
by
Kristina M. Nowitzki
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2008
Copyright 2008 Kristina M. Nowitzki
Object Description
| Title | The response of Allograft inflammatory factor-1 to neurotoxic injury, and its role as a secreted protein |
| Author | Nowitzki, Kristina M. |
| Author email | nowitzki@usc.edu; kristina.nowitzki@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-06-27 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-12-16 |
| Advisor (committee chair) | Tokes, Zoltan |
| Advisor (committee member) |
Weiner, Leslie P. Garner, Judy Mosteller, Raymond |
| Abstract | Allograft inflammatory factor-1 (AIF-1) is an evolutionary conserved protein important to inflammatory responses throughout the body including that of microglia in the central nervous system (CNS). In addition to critical intracellular roles in the activation of microglia and macrophages, AIF-1 can be secreted by these cells in response to inflammatory signals as well as soluble signals released by dying neurons. In response to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, we found increased levels of AIF-1 expression in cells clustered in the substantia nigra pars compacta (SNpc), the site of dopaminergic cell death. The number of these AIF-1 bright cells continued to increase even after neuronal cell death was complete. This increased expression of AIF-1 was restricted to resident microglia; flow cytometric analysis showed that infiltrating CD45hi leukocytes did not express high levels of AIF-1. Analysis of microglia ex vivo demonstrated the secretion of AIF-1 by these cells, lending support to a role for this molecule as an extracellular participant in the microglia response to neurotoxicity. To define a functional role for extracellular AIF-1 in CNS inflammation, we produced a recombinant mouse AIF-1 protein using a mammalian expression system and tested the functional activity of this protein both in vitro and in vivo. Intracerebral injection of recombinant AIF-1 into both the mouse striatum and midbrain led to activation of microglia and astrocytes near the site of injection, which was more prolonged and widespread compared to controls. Interestingly, ex vivo analysis of microglia showed no significant changes in inflammatory cytokine secretion whereas human peripheral blood mononuclear cells showed altered patterns in the secretion of TNF, IL-6, MCP-1, IL-8, and RANTES. This work shows for the first time that AIF-1 can be secreted by adult murine microglia and describes a new role for AIF-1 as a secreted molecule that can peripherally and local |
| Keyword | migroglia; MPTP; AIF-1; Allograft inflammatory factor-1 |
| 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-m1931 |
| Rights | Nowitzki, Kristina M. |
| 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-Nowitzki-2366 |
| Archival file | uscthesesreloadpub_Volume26/etd-Nowitzki-2366.pdf |
Description
| Title | Page 1 |
| Full text | THE RESPONSE OF ALLOGRAFT INFLAMMATORY FACTOR-1 TO NEUROTOXIC INJURY, AND ITS ROLE AS A SECRETED PROTEIN. by Kristina M. Nowitzki A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOCHEMISTRY AND MOLECULAR BIOLOGY) December 2008 Copyright 2008 Kristina M. Nowitzki |
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