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A novel role for thiols in the regulation of platelet function

Reddy, Emily C. (2013) A novel role for thiols in the regulation of platelet function. PhD thesis, Dublin City University.

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Abstract

Platelets are small, megakaryocyte-derived cell fragments that play a key role in haemostasis. Platelet receptors, in particular integrins, contain high numbers of reactive cysteines making them prime targets for thiol modifications. The plasma redox environment is controlled by low-molecular-weight thiol couples along with reactive oxygen/nitrogen species (RONS) and their respective scavengers. ‘Stress’ arises when an imbalance occurs within this tightly regulated redox system. The aim of this thesis is to investigate the role of thiol signalling in platelet function and examine the modulation of this signalling by the external redox environment. Previous work in our laboratory has demonstrated thiol/disulphide exchange to be critical to integrin IIb3 function. In this study, a significant increase in purified integrin IIb3 free thiols was observed upon activation. Integrin activation was inhibited in a reducing redox environment. Subsequently, it was found that platelet surface thiol population was increased upon stimulation with collagen only. Platelet activation by collagen was exclusively inhibited by a reducing external redox environment, with a concomitant modulation of the platelet surface thiol population. These results pointed to an exquisitely redox sensitive element of the collagen activation pathway, namely integrin 21. Furthermore, the phosphorylation state of VASP (vasodilator-stimulated phosphoprotein), a protein found downstream of integrin 21, was found to be affected by an external reducing redox environment in collagen stimulated platelets only. These results indicate modification of the receptor by the external environment can also impact on downstream, intra-platelet signalling events. These findings suggest a potential v novel therapeutic target for diseases with a characteristic imbalanced redox environment in which thromboembolic events are common, such an inflammatory bowel disease.

Item Type:Thesis (PhD)
Date of Award:November 2013
Refereed:No
Additional Information:Funded through the National Biophotonics and Imaging Platform, Ireland, funded by the Irish Government's Programme for Research in Third Level Institutions, Cycle 4, Ireland’s EU Structural Funds Programmes 2007 - 2013.
Supervisor(s):Forster, Robert J. and O Neill, Sarah and Keyes, Tia E.
Uncontrolled Keywords:Platelets; Thiol; Disulfide
Subjects:Biological Sciences > Biochemistry
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Research Initiatives and Centres > National Biophotonics and Imaging Platform Ireland (NBIPI)
Research Initiatives and Centres > National Centre for Sensor Research (NCSR)
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
Funders:Higher Education Authority
ID Code:19401
Deposited On:26 Nov 2013 11:49 by Tia Keyes. Last Modified 19 Sep 2015 01:02

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