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dc.contributor.authorSzendrey, Johnen
dc.date2016-08-17 14:34:53.538
dc.date.accessioned2016-08-24T17:35:19Z
dc.date.issued2016-08-24
dc.identifier.urihttp://hdl.handle.net/1974/14740
dc.descriptionThesis (Master, Biomedical & Molecular Sciences) -- Queen's University, 2016-08-17 14:34:53.538en
dc.description.abstractThe human ether-a-go-go-related gene (hERG) protein passes the rapidly activating delayed rectifier potassium channel (IKr), and malfunction of hERG protein/IKr is the primary cause of acquired long QT syndrome (LQTS). Autoimmune diseases are significantly correlated with prolonged QT intervals, for which autoantibodies have been implicated. The anti-Ro52 autoantibody is the most frequently evaluated, and importantly has been correlated with prolonged QT intervals. Pathological anti-Ro52-hERG interactions have been discussed as a mechanism for autoimmune disease-related LQTS. However, the mechanism is unclear, and it does not explain LQTS in autoimmune diseases which do not commonly express anti-Ro52. In this thesis, I investigated the effects of anti-Ro52 on hERG/IKr function. Through Western blot analysis, whole-cell patch-clamp, and immunofluorescence, I show that anti-Ro52 chronically (12 h) reduced hERG protein expression and hERG current by over 50%, but did not acutely block the channel. My work revealed a novel mechanism in which the Fc portion of anti-Ro52 interacts with the extracellular S5-pore linker of the channel to induce internalization through a tyrosine phosphorylation dependent pathway. This phenomenon extends beyond anti-Ro52 IgG, as other IgG, regardless of their antigen binding specificity, have the potential to reduce hERG expression/current. Rather, the ability of IgG to reduce hERG expression and current is dependent on the IgG subclass, as we show mouse IgG2A was the only mouse IgG subclass which reduced hERG expression. These results provide a novel explanation for autoimmune disease associated LQTS. It also has implications in the development of safe monoclonal antibody drugs.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsCreative Commons - Attribution - CC BYen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectAutoimmuneen
dc.subjecthERGen
dc.subjectLong QT Syndromeen
dc.subjectArrhythmiaen
dc.titleInvestigating the Mechanism of Autoimmune Disease Associated-LQTSen
dc.typethesisen
dc.description.restricted-thesisThis thesis contains original data which will be sent for publication in peer reviewed journals in the near future. I do not wish other groups within the field to be able to read this thesis so that they may not steal our intellectual ideas prior to our successful publication of our data.en
dc.description.degreeM.Sc.en
dc.contributor.supervisorZhang, Shetuanen
dc.contributor.departmentBiomedical and Molecular Sciencesen
dc.embargo.terms1825en
dc.embargo.liftdate2021-08-23
dc.degree.grantorQueen's University at Kingstonen


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