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Restoration of microglial transporter expression by NRF2 activation

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TitleInfo
Title
Restoration of microglial transporter expression by NRF2 activation
Name (type = personal)
NamePart (type = family)
Ritzau
NamePart (type = given)
Rachel Nicole
DisplayForm
Rachel Nicole Ritzau
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Aleksunes
NamePart (type = given)
Lauren
DisplayForm
Lauren Aleksunes
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2017
DateOther (qualifier = exact); (type = degree)
2017-10
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2017
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Activation of brain microglia can be both beneficial and detrimental during the pathogenesis of neuroinflammation. Healthy microglia will propagate short-term inflammation as a means of protecting the central nervous system (CNS) from ensuing injury. However, when this process becomes dysregulated, chronic neuroinflammation results, which further propagates injury to the neuro-environment. Consequently, chronic neuroinflammation results in neuronal death and loss of synapses, which will eventually culminate in neurodegeneration. The principal aim of this dissertation research was to determine whether adaptive changes in the expression of microglial efflux transporters during a neuro-inflammatory state could be attenuated by activation of the antioxidant Nrf2 pathway. The primary function of efflux transporters is to remove both endogenous and exogenous substrates from the cell. This efflux can prevent the accumulation of toxic substrates and ensure proper cell-cell communication. Our laboratory has previously demonstrated that increasing concentrations of the bacterial endotoxin, lipopolysaccharide (LPS), in immortalized mouse BV-2 microglial cells decreases the expression and function of the multidrug resistance proteins 1a and 1b (Mdr1a/1b) and the breast cancer resistance protein (Bcrp) transporter while increasing the expression of several multidrug resistance-associated protein (Mrp) efflux transporters. These findings were confirmed in the present study using the same model of microglial activation. Further, studies were conducted to assess the ability of a Nrf2 activator, dimethyl fumarate (DMF, Tecfidera), to mitigate the down-regulation of efflux transporters in mouse microglial cells. Dose- and time-course studies for LPS and DMF were performed in BV-2 cells. Activation of the Nrf2 pathway was assessed by quantifying Nrf2 binding to a prototypical antioxidant response element and the expression of the Nrf2 target genes, NAD(P)H quinone oxidoreductase 1 (Nqo1) and heme oxygenase-1 (Ho-1). Microglial cells were co-treated with both LPS and DMF for 12 and 24 hr and profiled for expression of cytokines, Nrf2 targets and efflux transporters using qPCR and western blotting. In general, the treatment of BV-2 cells with LPS decreased the expression of Mdr1a, Mdr1b, and Bcrp. LPS treatment also up-regulated the levels of Mrp1 and Mrp5 mRNAs. Co-treatment of DMF with LPS prevented mRNA changes in cytokines and efflux transporters and, for Bcrp, restored protein expression to that observed in vehicle-treated BV-2 cells. Together, this research establishes a connection between neuroinflammation, Nrf2 activation, and efflux transporter expression that may be exploited pharmacologically to restore microglial functions.
Subject (authority = RUETD)
Topic
Toxicology
Subject (authority = ETD-LCSH)
Topic
Microglia
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_8516
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (ix, 83 p. : ill.)
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Rachel Nicole Ritzau
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T3X63R34
Genre (authority = ExL-Esploro)
ETD graduate
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Ritzau
GivenName
Rachel
MiddleName
Nicole
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2017-10-03 16:30:14
AssociatedEntity
Name
Rachel Ritzau
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
Type
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Name
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.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical

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DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2017-10-11T18:14:57
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2017-10-11T18:14:57
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