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Regulation of efflux transporter expression and function in neural injury and inflammation
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Gibson, Christopher. Regulation of efflux transporter expression and function in neural injury and inflammation. Retrieved from https://doi.org/doi:10.7282/T3377BF2

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TitleRegulation of efflux transporter expression and function in neural injury and inflammation
NameGibson, Christopher (author); Cooper, Keith R (chair); Aleksunes, Lauren M (internal member); Richardson, Jason R (internal member); Reuhl, Kenneth (internal member); Wu, Long-Jun (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2015
Other Date2015-01 (degree)
SubjectToxicology, Parkinson's disease, Herbicides--Health aspects, Brain--Wounds and injuries
Extent1 online resource (xiii, 204 p. : ill.)
DescriptionParkinson disease (PD) is the second most common neurodegenerative disorder of aging worldwide. There is mounting evidence that both genetic and environmental factors contribute to the development of PD. The main hallmarks of PD pathology include loss of dopamine neurons in the substantia nigra pars compacta (SNc), activation of microglia, production of pro-inflammatory cytokines, and accumulation of oxidized lipids and proteins. Epidemiologic studies suggest that exposure to pesticides may contribute to the development of PD, particularly in individuals with a genetic polymorphism in the Multidrug Resistance Transporter 1 (MDR1) which removes chemicals from the brain. The herbicide paraquat is used to study features of PD in rodents, namely dopamine neuron loss and microglial activation. The work presented in this dissertation examines the role that the MDR1 efflux transporter plays in preventing neuronal death from paraquat-induced toxicity, as well as immunologic factors that modulate this protective function. Following exposure to a single dose of paraquat, mice lacking the Mdr1a/1b genes have extensive dopamine neuron loss and microglial activation in the SNc, whereas wild-type mice require at least two doses. It is hypothesized that MDR1 is an efflux transporter for paraquat thereby preventing paraquat accumulation and toxicity in the brain. Experiments using an MDR1-transfected cell line or human cerebral endothelial cells naturally expressing MDR1 demonstrate that accumulation of paraquat is reduced in cells with functional MDR1. Work in this dissertation also investigates the regulation of Mdr1 and other transporters in microglia. Activation of microglia with lipopolysaccharide (LPS) leads to the down-regulation of Mdr1 and Bcrp and up-regulation of Mrp1 and Mrp5 transporters. Using fluorescent substrates, it is observed that LPS activation of microglia reduces the function of Mdr1 and Bcrp. Lastly, the mechanisms that regulate Mdr1 in activated microglia are explored. Using inhibitors and activators of several cellular pathways, including NF-κB, Nrf2, and cytokines, it is found that Mdr1 is strongly influenced by TNF and NF-κB pathways. This thesis demonstrates the ability of the Mdr1 transporter to protect against pesticide-induced neural injury and characterizes the role of inflammatory factors in regulating Mdr1 expression and function in microglia and the blood-brain barrier.
NotePh.D.
NoteIncludes bibliographical references
Noteby Christopher Gibson
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3377BF2
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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