Interleukin-17A (IL-17A) enhances axonal regeneration and mitochondrial function of normal and diabetic sensory neurons

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dc.contributor.authorHabash, Tarek
dc.contributor.examiningcommitteeAlbensi, Benedict (Pharmacology and Therapeutics) Czubryt, Michael (Physiology)en_US
dc.contributor.supervisorFernyhough, Paul (Pharmacology and Therapeutics)en_US
dc.date.accessioned2014-08-27T17:01:09Z
dc.date.available2014-08-27T17:01:09Z
dc.date.issued2014-08-27
dc.degree.disciplinePharmacology and Therapeuticsen_US
dc.degree.levelMaster of Science (M.Sc.)en_US
dc.description.abstractRationale and hypothesis: Diabetic neuropathy involves dying back of nerve endings that reflects impairment in axonal plasticity and regenerative nerve growth. Metabolic changes in diabetes can lead to a dysregulation of hormonal mediators, such as cytokines. Thus I studied the effect of interleukin-17A (IL-17A), a proinflammatory cytokine produced by T-cells, on the phenotype of sensory neurons derived from control or diabetic rats. I hypothesized that IL-17A induces neurite outgrowth in sensory neurons through signaling pathways that enhance mitochondrial function. IL-17A can also reverse impaired nerve regeneration associated with diabetes Objectives: Determine the ability of IL-17A to enhance neurite outgrowth in cultured sensory neurons. Investigate the signalling pathways activated by IL-17A and mechanistically link to neurite outgrowth. Study the ability of IL-17A to improve mitochondrial function of sensory neurons (since axon outgrowth consumes high levels of ATP). Methodology: Cultured adult dorsal root ganglia (DRG) sensory neurons derived from age matched control or streptozotocin (STZ)-induced type 1 diabetic rats were fixed and stained for fluorescent imaging to determine total neurite outgrowth. Western blotting determined the levels of MAPK and PI-3K activation by IL-17A and for measuring levels of proteins of mitochondrial oxidative phosphorylation pathway. Mitochondrial bioenergetic function was tested in cultured DRG neurons using the Seahorse XF Analyzer. Results: I found that IL-17A (10 ng/ml; P<0.05) significantly increased total neurite outgrowth in cultures derived from both control and STZ-diabetic rat models. This enhancement was mediated by IL-17A-dependent activation of MAPK and PI-3K pathways with maximal effect at 15 minutes (P<0.05). Pharmacological blockade of one of these activated pathways led to total inhibition of neurite outgrowth. IL-17A improved mitochondrial bioenergetic function of sensory neurons. Bioenergetics function was associated with augmented expression of proteins of mitochondrial oxidative phosphorylation. Conclusion: IL-17A enhanced axonal plasticity through activation of MAPK and PI-3K pathways and was associated with augmented mitochondrial bioenergetics function in sensory neuronsen_US
dc.description.noteOctober 2014en_US
dc.identifier.urihttp://hdl.handle.net/1993/23900
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectDiabetesen_US
dc.subjectNeuropathyen_US
dc.subjectSensoryen_US
dc.subjectNeuronsen_US
dc.subjectMitochondriaen_US
dc.titleInterleukin-17A (IL-17A) enhances axonal regeneration and mitochondrial function of normal and diabetic sensory neuronsen_US
dc.typemaster thesisen_US
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