Immune and stress factors in the pathophysiology of the mdx mouse model of Duchenne Muscular Dystrophy

Simple item page
dc.check.embargoformatNot applicableen
dc.check.infoNo embargo requireden
dc.check.opt-outNot applicableen
dc.check.reasonNo embargo requireden
dc.check.typeNo Embargo Required
dc.contributor.advisorO'Malley, Dervlaen
dc.contributor.authorManning, Jennifer
dc.contributor.funderMuscular Dystrophy Irelanden
dc.contributor.funderPhysiology, College of Medicine and Health, University College Corken
dc.date.accessioned2015-08-13T11:21:57Z
dc.date.available2015-08-13T11:21:57Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractDuchenne Muscular Dystrophy (DMD) is a fatal multi-system neuromuscular disease caused by loss of dystrophin. The loss of dystrophin from membranes of contractile muscle cells and the dysregulation of the DAPC, induces chronic inflammation due to tissue necrosis and eventual replacement with collagen which weakens muscular force and strength. Dystrophin deficiency may cause under-diagnosed features of DMD include mood disorders such as depression and anxiety and dysfunction of the gastrointestinal tract. The first study in the thesis examined mood in the dystrophin-deficient mdx mouse model of DMD and examined the effects of the tri-cyclic antidepressant, amitriptyline on behaviours. Amitriptyline had anti-depressant and anxiolytic effects in the mdx mice possibly through effects on stress factors such as corticotrophin-releasing factor (CRF). This antidepressant also reduced skeletal muscle inflammation and caused a reduction in circulating interleukin (IL)-6 levels. In the second and third studies, we specifically blocked IL-6 signalling and used Urocortin 2, CRFR2 agonist to investigate their potential as therapeutic targets in mdx mice pathophysiology. Isometric and isotonic contractile properties of the diaphragm, were compared in mdx mice treated with anti IL-6 receptor antibodies (anti IL-6R) and/or Urocortin 2. Deficits in force production, work and power detected in mdx mice were improved with treatment. In study three I investigated contractile properties in gastrointestinal smooth muscle. As compared to wild type mice, mdx mice had slower faecal transit times, shorter colons with thickened muscle layers and increased contractile activity in response to recombinant IL-6. Blocking IL-6 signalling resulted in an increase in colon length, normalised faecal output times and a reduction in IL-6-evoked contractile activity. The findings from these studies indicate that for both diaphragm and gastrointestinal function in a dystrophin-deficient model, targeting of IL-6 and CRFR2 signalling has beneficial therapeutic effects.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationManning, J. 2014. Immune and stress factors in the pathophysiology of the mdx mouse model of Duchenne Muscular Dystrophy. PhD Thesis, University College Cork.en
dc.identifier.endpage245
dc.identifier.urihttps://hdl.handle.net/10468/1902
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, Jennifer Manning.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectMuscleen
dc.subjectMuscular Dystrophyen
dc.subjectStressen
dc.subjectInflammationen
dc.subjectInterleukin - 6en
dc.thesis.opt-outfalse
dc.titleImmune and stress factors in the pathophysiology of the mdx mouse model of Duchenne Muscular Dystrophyen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnameDoctor of Medicineen
ucc.workflow.supervisord.omalley@ucc.ie
Files
Original bundle
Now showing 1 - 2 of 2
Thumbnail Image
Name:
Thesis Abstract.pdf
Size:
7.32 KB
Format:
Adobe Portable Document Format
Description:
Abstract
Thumbnail Image
Name:
ManningJPhD.pdf
Size:
4.78 MB
Format:
Adobe Portable Document Format
Description:
Full Text E-thesis
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
5.62 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Doctoral Theses
College of Medicine and Health - Doctoral Theses
Physiology - Doctoral Theses