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dc.contributor.authorRookyard, Alexander
dc.date.accessioned2023-10-25T04:06:05Z
dc.date.available2023-10-25T04:06:05Z
dc.date.issued2023en_AU
dc.identifier.urihttps://hdl.handle.net/2123/31808
dc.description.abstractCardiovascular disease is the leading cause of death worldwide with a mortality rate of 17 million people per annum. Ischemic heart disease is the largest contributor to this mortality rate. Ischemia is the loss of an adequate supply of oxygenated blood to the heart. This severely impairs heart function. During ischemia / reperfusion (I/R) the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is sufficient to cause cellular damage. ROS/RNS can alter proteins via posttranslational modification (PTM) of Cys residues. Redox PTM of Cys can be broken down into two groups. Those that are considered biologically ‘reversible’ and those that are considered biologically ‘irreversible’. Irreversible modifications are associated with protein dysfunction and proteolytic degradation. Current techniques to measure Cys PTMs are limited to few methods. To overcome this, we applied an enrichment technique for irreversibly modified Cys peptides to profile sites of irreversible Cys redox PTM in rat hearts subjected to ex vivo Langendorff perfusion and I/R injury. Quantitation was achieved using a novel parallel reaction monitoring mass spectrometry (PRM-MS) strategy on Cys peptides. We correlated changes to specific Cys peptide redox status with a targeted metabolomics approach. We next applied this approach to investigate ROS/RNS imbalance in the diabetic heart. Increased oxidative stress via ROS/RNS has been implicated in the aetiology of the diabetic heart, however, the targets of ROS/RNS are poorly defined. We utilised a rodent model of T2DM to examine hearts by Langendorff perfusion. Irreversibly modified Cys were largely increased in abundance in diabetic hearts under baseline conditions. This thesis has developed methods suitable for the routine identification and quantification of sites of irreversible Cys redox PTMs. Identification of such sites provides targets for specific antioxidant therapy to preserve enzyme functions during pathogenesis.en_AU
dc.language.isoenen_AU
dc.subjectProteomicsen_AU
dc.subjectMass Spectrometryen_AU
dc.subjectRedox Biologyen_AU
dc.subjectCysteine Post Translational Modificationen_AU
dc.subjectIschemia Reperfusion Injuryen_AU
dc.subjectDiabetesen_AU
dc.titleQuantitative Proteomics of Cysteine Redox Post-Translational Modificationsen_AU
dc.typeThesis
dc.type.thesisDoctor of Philosophyen_AU
dc.rights.otherThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
usyd.facultySeS faculties schools::Faculty of Science::School of Life and Environmental Sciencesen_AU
usyd.degreeDoctor of Philosophy Ph.D.en_AU
usyd.awardinginstThe University of Sydneyen_AU
usyd.advisorCordwell, Stuart


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