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

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dc.contributor.advisor O'Keeffe, Gerard W. en
dc.contributor.author McKelvey, Laura
dc.date.accessioned 2013-12-19T16:07:25Z
dc.date.available 2013-12-19T16:07:25Z
dc.date.issued 2013
dc.date.submitted 2013
dc.identifier.citation McKelvey, L. 2013. The role of glucocorticoid-induced tumour necrosis factor receptor in developing mouse sympathetic neurons. PhD Thesis, University College Cork. en
dc.identifier.endpage 192
dc.identifier.uri http://hdl.handle.net/10468/1291
dc.description.abstract Hereditary 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.sponsorship Science Foundation Ireland (SFI Grant R13589) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Laura McKelvey en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject GITR en
dc.subject Mouse en
dc.subject Sympathetic neurons en
dc.subject Growth en
dc.subject.lcsh Neurons--Growth en
dc.subject.lcsh Neurons--Physiology en
dc.title The role of glucocorticoid-induced tumour necrosis factor receptor in developing mouse sympathetic neurons en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en
dc.check.info No embargo required en
dc.description.version Accepted Version
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en
dc.internal.school Biosciences Institute en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
ucc.workflow.supervisor g.okeeffe@ucc.ie
dc.internal.conferring Autumn Conferring 2013 en


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