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dc.contributor.authorBarth, Brian M.
dc.date.accessioned2018-08-06T22:37:29Z
dc.date.available2018-08-06T22:37:29Z
dc.date.issued2009
dc.identifier.urihttp://hdl.handle.net/11122/8999
dc.descriptionDissertation (Ph.D.) University of Alaska Fairbanks, 2009
dc.description.abstractInflammation is a major component of acute and chronic pathologies of the central nervous system, including psychiatric disorders. Microglia respond to pathogens, injury, and toxins by secreting inflammatory mediators including pro-inflammatory cytokines in an event known as neuroinflammation. This thesis research investigated a link between neuroinflammation and oxidative stress, and ultimately neurodegeneration. The cytokine tumor necrosis factor alpha was shown to stimulate a neuronal NADPH oxidase (NOX), specifically by stimulating the production of ceramide and ceramide-1-phosphate via Mg 2+-neutral sphingomyelinase (Mg2+-nSMase) and ceramide kinase. Intriguingly, glucosylceramide blocked NOX activation, linking ceramide neutralization directly to a decline in oxidative stress. Most importantly, NOX activity interfered with actin and sphingosine kinase-1 via oxidation, demonstrating a positive and detrimental feedback mechanism that impedes neuronal survival pathways. Interestingly, crude extracts from wild Alaskan bog blueberries showed the ability to interfere with Mg2+-nSMase, demonstrating a specific neuroprotective property of the berry. Altogether, this thesis research defined a key neuronal pathway linking inflammation to oxidative stress via ceramide metabolism, potentially allowing for future therapeutic development to improve neuronal function and survival.
dc.subjectBiochemistry
dc.subjectNeurosciences
dc.subjectMolecular biology
dc.titleCeramide Metabolism Regulates A Neuronal Nadph Oxidase Influencing Neuron Survival During Inflammation
dc.typeDissertation
dc.type.degreephd
dc.identifier.departmentDepartment of Chemistry and Biochemistry
refterms.dateFOA2020-03-06T01:04:37Z


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