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The effects of genetic polymorphisms on recovery after repeated mild traumatic brain injury in a mouse model and personalized treatment approaches
Descriptive
TitleInfo
Title
The effects of genetic polymorphisms on recovery after repeated mild traumatic brain injury in a mouse model and personalized treatment approaches
Name
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Giarratana
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Anna Obee
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1987-
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Anna Obee Giarratana
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author
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Janet
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Janet Alder
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Advisory Committee
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chair
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Thakker-Varia
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Smita
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Smita Thakker-Varia
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Advisory Committee
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internal member
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Millonig
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(type = given)
James
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James Millonig
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Advisory Committee
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internal member
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(type = personal)
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(type = family)
Shreiber
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(type = given)
David
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David Shreiber
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Advisory Committee
Role
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internal member
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(type = family)
Levison
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Steven
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Steven Levison
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Advisory Committee
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(authority = RULIB)
outside member
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Rutgers University
Role
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(authority = RULIB)
degree grantor
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School of Graduate Studies
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school
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Text
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theses
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2019
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2019-05
Language
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English
Abstract
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Traumatic Brain Injury (TBI) is a serious and potentially life-threatening clinical problem. In 2013, there were 2.5 million TBIs in the United States, 50,000 of which led to death and 70,000 of which led to permanent neurological damage. Clinicians have long noticed that certain patients have worse recovery than others after TBI and identifying what makes some patients more susceptible is a vital step in understanding the underlying mechanisms through which TBI causes its deleterious effects. In this study, we sought to determine the effect of specific single nucleotide polymorphisms (SNPs) on recovery after TBI, and to investigate the underlying mechanisms that may be a factor. This knowledge can be used to explore personalized approaches to treatment of TBI. We have investigated cellular and behavioral outcomes in genetically engineered mice with either the Brain-derived neurotrophic factor (BDNF) Val66Met or ApoE4 polymorphism following repeated mild TBI (rmTBI) using a lateral fluid percussion injury model. We have found that relative to injured Val66Val and ApoE3 carriers, injured Val66Met and ApoE4 carriers have a larger injury volume and increased levels of neurodegeneration, apoptosis, p-tau, activated microglia, and gliosis in the cortex and/or hippocampus at 1 and/or 21 days post injury (DPI) as well as altered levels of BDNF. As a result, we have concluded that the ApoE4 and the Val66Met genetic polymorphisms are a risk factor for poor outcomes after rmTBI. Using this information, we developed a personalized approach to treating genetically susceptible individuals by targeting the pathway altered in those genotypes. In the Val66Met mice, we used an AAV-BDNF virus to overexpress wildtype BDNF in the cortex and hippocampus and investigated outcomes at the 21 DPI timepoint. In the ApoE mice, we used Bryostatin-1, a PKCε activator that has been shown to rapidly increase BDNF levels, and investigated outcomes at the 1 DPI timepoint. We have shown that these interventions are able to improve cellular as well as motor and cognitive behavior outcomes at these timepoints. This study lays the groundwork for further investigation into the genetics that play a role in recovery after rmTBI and highlights the role that personalized therapeutics may be able to play in recovery for susceptible individuals.
Subject
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Topic
Traumatic brain injury
Subject
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Topic
Neuroscience
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Title
Rutgers University Electronic Theses and Dissertations
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ETD_9761
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application/pdf
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text/xml
Extent
1 online resource (xvii, 177 pages) : illustrations
Note
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Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Subject
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Topic
Brain -- Wounds and injuries
Subject
(authority = LCSH)
Topic
Single nucleotide polymorphisms
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Title
School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
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doi:10.7282/t3-44fh-dj05
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Giarratana
GivenName
Anna
MiddleName
Obee
Role
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Permission or license
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2019-04-11 11:05:56
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Name
Anna Giarratana
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Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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Embargo
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2019-05-31
DateTime
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2021-05-30
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 30th, 2021.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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