The role of glucocorticoid-induced tumour necrosis factor receptor in developing mouse sympathetic neurons

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dc.check.embargoformatNot applicableen
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dc.contributor.advisorO'Keeffe, Gerard W.en
dc.contributor.authorMcKelvey, Laura
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2013-12-19T16:07:25Z
dc.date.available2013-12-19T16:07:25Z
dc.date.issued2013
dc.date.submitted2013
dc.description.abstractHereditary sensory autonomic neuropathy IV (HSAN IV) is an autosomal recessive disorder characterised by inability to feel pain and anhidrosis and is a consequence of defective NGF/TrkA signalling and growth of sensory and sympathetic neurons. Glucocortiocoid-induced tumour necrosis factors receptor (GITR), a transmembrane protein, activated by its specific ligand, GITRL, is well known for its role in the regulation of innate and acquired immune system responses. Recently, GITR was found to be required for NGF-dependant and extracellular signal-related kinase 1/2 (ERK1/2)-induced neurite growth and target innervation in the developing sympathetic nervous system (SNS). Given this novel role of GITR, it is possible that strategies targeting GITR have potential therapeutic benefit in promoting neurite growth in autonomic neuropathies such as HSAN IV. Using P1 mouse SCG neurons as a model, in addition to various SCG cell treatments, knock down models and transfection methods, we investigated whether GITR increases the sensitivity of sympathetic neurons to NGF; the region of GITR required for the enhancement of NGF-promoted growth, the signalling pathways downstream of GITR and how extensively GITR is involved in regulating peripheral innervation of the SNS. Results indicate that the region responsible for the growth promoting effects of GITR lies in its juxtamembrane intracellular region (here termed the growth promoting domain (GPD)) of GITR. The GPD of GITR activates ERK1/2 and inhibits nuclear factor kappa B (NF-κB) in an inverse fashion to provide an optimal cellular growth environment for P1 SCG neurons. While deleting the GPD of GITR had no effect on TrkA expression, constitutive phosphorylation of specific sites in the GPD reduced TrkA expression indicating a possible role for GITR in increasing the sensitivity of SCG neurons to NGF by the regulation of these sites, TrkA expression and subsequent NGF/TrkA binding. GITR appears to be heterogeneously required for NGF-promoted target innervation of SCG neurons in some organs, implying additional factors are involved in extensive NGF-target innervation of the SNS. In conclusion, this study answers basic biological questions regarding the molecular mechanism behind the role of GITR in the development of the SNS, and provides a basis for future research if GITR modulation is to be developed as a strategy for promoting axonal growth.en
dc.description.sponsorshipScience Foundation Ireland (SFI Grant R13589)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMcKelvey, L. 2013. The role of glucocorticoid-induced tumour necrosis factor receptor in developing mouse sympathetic neurons. PhD Thesis, University College Cork.en
dc.identifier.endpage192
dc.identifier.urihttps://hdl.handle.net/10468/1291
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2013, Laura McKelveyen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectGITRen
dc.subjectMouseen
dc.subjectSympathetic neuronsen
dc.subjectGrowthen
dc.subject.lcshNeurons--Growthen
dc.subject.lcshNeurons--Physiologyen
dc.thesis.opt-outfalse
dc.titleThe role of glucocorticoid-induced tumour necrosis factor receptor in developing mouse sympathetic neuronsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisorg.okeeffe@ucc.ie
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