The innate immune response serves as a defense against infection, but it can also have negative consequences, particularly when it affects the central nervous system (CNS). Interferon is a key mediator of the innate immune response, and is responsible for the induction of a number of interferon-stimulated genes (ISGs). Transcripts encoding ADAR1, a double-stranded RNA-specific adenosine deaminase involved in the adenosine-to-inosine (A-to-I) editing of mammalian RNAs, are alternatively spliced in response to interferon, resulting in induction of an interferon- inducible protein isoform (p150) of ADAR1 that is up-regulated in both cell culture and in vivo model systems in response to pathogen or interferon stimulation. In contrast to other tissues, p150 is expressed at extremely low levels in the brain and it is unclear what role, if any, this isoform plays in the innate immune response of the CNS. ADAR1s involvement in editing RNA substrates critical for CNS function led us to in- vestigate the expression of ADAR1 isoforms in response to viral infection of the brain and to explore possible alterations in A-to-I editing profiles for CNS-specific ADAR targets. We used a neurotropic strain of reovirus to infect neonatal mice and exploit the endogenous interferon system. Subsequently, we characterized ADAR1 isoform expression in discrete brain regions using multiple, complementary methods of analysis.

We also used a multiplexed, high-throughput sequencing strategy to quantify A-to-I editing profiles in the same brain regions. While intracranial injection of reovirus resulted in a widespread increase in the expression of ADAR1 (p150) in the CNS and peripheral organs, significant changes in site-specific A-to-I conversion were quite limited, suggesting the possibility of more complex regulatory mechanisms for p150 editing or non-editing related functions for this interferon-sensitive isoform of ADAR1.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11242014-215051 |
| Date | 05 December 2014 |
| Creators | Hood, Jennifer Lyn |
| Contributors | Dr. Ron Emeson, Dr. Jeff Conn, Dr. Terry Dermody, Dr. Randy Blakely |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11242014-215051/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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