Alshehri, Osama Mohammed D (2016). The role of GPVI and CLEC-2 in platelet activation by miscellaneous ligands. University of Birmingham. Ph.D.
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Alshehri16PhD.pdf
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Abstract
Platelets are an essential factor in wound repair and blood clotting, where exposed sub-endothelial extracellular matrix (ECM) proteins induce activation during vascular injury. However, platelets can also be activated by a diverse range of stimuli that share little-to-no resemblance in structure to each other, or to recognized ligands of platelet receptors. These stimuli include diesel exhaust particles (DEP), various peptides including 4N1-1 and Champs, lipoproteins such as PAM3-CSK4, and large polysaccharides for example, fucoidan, and dextran.
In this thesis, I demonstrate that this seemingly miscellaneous group of stimuli cause aggregation of human and mouse platelets through Src and Syk tyrosine kinases in association with stimulus-specific tyrosine phosphorylation of the GPVI/FcRγ-chain complex and/or CLEC-2. A critical role for GPVI and/or CLEC-2 in mediating aggregation is shown using platelets from receptor-deficient mouse platelets. Additionally, in double deficient mouse platelets these stimuli activate Src tyrosine kinases independent of GPVI and CLEC-2. DEP, fucoidan and dextran were shown to activate transfected GPVI or CLEC-2 in a cell line model. However, 4N1-1, Champs and PAM3-CSK4 did not activate transfected GPVI or CLEC-2 in a cell line model, nor could they bind to recombinant forms of either receptor. In addition, I demonstrate the unexpected observation that fibrin also activates GPVI revealing a new stage of haemostasis in which the generation of fibrin from fibrinogen reinforces platelet activation.
Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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Award Type: | Doctorates > Ph.D. | |||||||||
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College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | |||||||||
School or Department: | Institute of Cardiovascular Sciences | |||||||||
Funders: | None/not applicable | |||||||||
Subjects: | Q Science > QH Natural history > QH301 Biology | |||||||||
URI: | http://etheses.bham.ac.uk/id/eprint/6880 |
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