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dc.contributor.advisorCampanucci, Veronica A.en_US
dc.creatorChandna, Andrewen_US
dc.date.accessioned2013-09-06T12:00:17Z
dc.date.available2013-09-06T12:00:17Z
dc.date.created2013-08en_US
dc.date.issued2013-09-05en_US
dc.date.submittedAugust 2013en_US
dc.identifier.urihttp://hdl.handle.net/10388/ETD-2013-08-1174en_US
dc.description.abstractDiabetes, which is characterized by elevated plasma glucose, can have a devastating effect on peripheral nerves frequently leading to the clinical symptoms of neuropathy. Diabetic autonomic neuropathy (DAN) results from damage to autonomic nerves, and the most troubling forms of DAN often lead to cardiovascular abnormalities and premature death. Despite the prevalence of DAN and the impact to quality and life expectancy, the precise mechanisms underlying these pathologies are poorly understood. Recently, a new model for the onset of DAN was proposed where hyperglycemia-induced oxidative stress inactivates nicotinic acetylcholine receptors (nAChRs), the main receptor driving autonomic synaptic transmission at sympathetic ganglia. This inactivation leads to the depression of synaptic transmission, and consequently triggers the onset of autonomic neuropathy in diabetic mice. However, the source and pathways contributing to the elevation of reactive oxygen species (ROS) and oxidative stress remained unclear. In recent years it has been shown that the accelerated formation of advanced glycation end products (AGEs) and activation of their receptor (RAGE) in diabetes play a major role in the induction of oxidative stress in sensory nerve damage. Thus we hypothesized that the activation and up-regulation of RAGE during high glucose conditions is a major source of ROS production in sympathetic neurons leading to the inactivation of nAChRs and autonomic malfunction. In this thesis we show for the first time that RAGE is expressed in cultured sympathetic neurons and is also up-regulated during high glucose conditions. Our results further demonstrate that direct RAGE activation by its natural ligands leads to an increase in cytoplasmic ROS which in turn induces the inactivation of nAChRs in sympathetic neurons. We also report that high glucose-induced ROS generation and subsequent inactivation of nAChRs is prevented in sympathetic neurons from RAGE knock-out mice. The results of this dissertation suggest RAGE to be a pivotal source of ROS production leading to the functional deficits observed in sympathetic neurons during high glucose conditions.en_US
dc.language.isoengen_US
dc.subjectRAGEen_US
dc.subjectdiabetesen_US
dc.subjectoxidative stressen_US
dc.subjectneuropathyen_US
dc.subjectsympathetic nervous systemen_US
dc.subjectnAChRsen_US
dc.titleDisruption of RAGE signaling prevents sympathetic neuron malfunction in high glucose conditionsen_US
thesis.degree.departmentPhysiologyen_US
thesis.degree.disciplinePhysiologyen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelMastersen_US
thesis.degree.nameMaster of Science (M.Sc.)en_US
dc.type.materialtexten_US
dc.type.genreThesisen_US
dc.contributor.committeeMemberHowland, John G.en_US
dc.contributor.committeeMemberMulligan, Sean J.en_US
dc.contributor.committeeMemberBekar, Lane K.en_US
dc.contributor.committeeMemberWest, Nigel H.en_US


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