Show simple item record

dc.contributor.advisorPalmer, Timothy M.
dc.contributor.advisorRiches-Suman, Kirsten
dc.contributor.advisorElies, Jacobo
dc.contributor.authorMoshapa, Florah T.
dc.date.accessioned2024-01-02T13:49:38Z
dc.date.available2024-01-02T13:49:38Z
dc.date.issued2021
dc.identifier.urihttp://hdl.handle.net/10454/19744
dc.description.abstractNeointimal hyperplasia (NIH) is a cardiovascular disease characterised by increased smooth muscle cell (SMC) inflammation and proliferation. Suppressor of cytokine signalling 3 (SOCS3) limits Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways involved in vascular remodelling but is limited by its short biological half-life. Therefore, mutation of all 9 Lys residues that are potential sites of ubiquitylation to Arg should produce a mutated SOCS3 resistant to ubiquitin-mediated proteasomal degradation (“Lys-less” SOCS3). This study hypothesise that enhancing SOCS3 stability and limiting JAK/STAT signalling may provide sustained inhibition of the vascular remodelling in NIH. Lentiviral transduction of WT and Lys-less SOCS3 in human saphenous vein (HSVSMCs) was highly efficient after 48 hours (>97%) and was sustained over 2 weeks. Lys-less SOCS3 was resistant to ubiquitylation contrary to WT-transduced HSVECs, and Lys-less SOCS3 was more stable (t1/2=4h) than WT (t1/2<4h) (n=6, P<0.001) in HSVSMCs. In HSVSMCs, both Lys-less SOCS3 and WT inhibited sIL-6Rα/IL-6 mediated STAT3 activation but not extracellular signal regulated protein kinase 1/2 (ERK1/2) by 80±7% (Lys-lessSOCS3/pSTAT3) and 74±6% (WT/pSTAT3) (n=3, P<0.05) and similarly inhibited PDGF-mediated STAT3 activation but not ERK1/2 by 67±17% (Lys-less SOCS3/pSTAT3) and 72±18% (WT/pSTAT3) (n=3, P<0.05). Functionally, Lys-less SOCS3 and WT were equivalent in inhibiting sIL-6Rα/IL-6 and PDGF-induced proliferation, whilst having no effects on PDGF-induced migration in HSVSMCs. Lys-less SOCS3 can be successfully transduced into primary HSVSMCs. It is more stable than WT yet retains its functional ability to ameliorate pro-inflammatory signalling and SMC proliferation, making it an attractive option for developing treatment of NIH.en_US
dc.description.sponsorshipUniversity of Botswanaen_US
dc.language.isoenen_US
dc.rights<a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>.eng
dc.subjectNeointimal hyperplasia (NIH)en_US
dc.subjectCytokine signalling 3 (SOCS3)en_US
dc.subjectJanus kinase (JAK)en_US
dc.subjectJAK/STAT signallingen_US
dc.subjectSignal transducer and activator of transcription (STAT)en_US
dc.subjectHuman saphenous veinen_US
dc.subjectCell migrationen_US
dc.subjectCell proliferationen_US
dc.subjectCardiovascular diseaseen_US
dc.subjectSmooth muscle cellen_US
dc.titleSuppressor of cytokine signalling 3 (SOCS3) turnover and regulation of human saphenous vein smooth muscle cell signalling and functionen_US
dc.type.qualificationleveldoctoralen_US
dc.publisher.institutionUniversity of Bradfordeng
dc.publisher.departmentSchool of Pharmacy and Medical Sciences. Faculty of Life Sciencesen_US
dc.typeThesiseng
dc.type.qualificationnamePhDen_US
dc.date.awarded2021
refterms.dateFOA2024-01-02T13:49:38Z


Item file(s)

Thumbnail
Name:
08016776 Florah Moshapa Final ...
Size:
9.526Mb
Format:
PDF
Description:
PhD Thesis

This item appears in the following Collection(s)

Show simple item record