Calaminus, Simon (2007). Glycoprotein receptor mediated regulation of platelet morphology. University of Birmingham. Ph.D.
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Abstract
Spreading platelets sequentially form filopodia, lamellipodia, and stress fibres. This thesis demonstrates the formation of each actin structure in spread platelets, and in addition the formation of a novel actin structure, which I have termed an actin nodule. Actin nodules require Src kinase activation, and actin polymerisation, but are negatively correlated to ROCK and myosin-II activation.
This thesis has investigated the role of WAVE-l, Rho kinase (ROCK) and myosin-II in spreading and aggregate stability in vitro and in vivo. ROCK or myosin-II inhibition, prevents stress fibre formation leading to appearance of splits and holes (termed fenestrations) in spread platelets on collagen. In addition, ROCK or myosin-II inhibition compromises aggregate stability on collagen at arterial rates of flow. Lamellipodia formation is inhibited in WAVE-rl - platelets spread on CRP, whilst shape change and aggregation downstream of GPVI is severely disrupted. However, GPCR agonists induce full lamellipodia formation on fibrinogen in WAVE-I-I. Aggregate formation on collagen under arterial rates of flow is unaffected further indicating . WAVE-2 can compensate for WAVE-I. Thus, WAVE-l maybe differentially regulated downstream of GPCR and glycoprotein signalling.
The actin regulatory proteins, Spin-90, Β-Pix and Nck are tyrosine phosphorylated by multiple platelet agonists, but do not form a complex upon platelet adhesion. However, B-Pix is heavily phosphorylated downstream of the collagen receptor integrin, a2BI. I speculate B-Pix may play an important role in connecting PLCyl to Rac activation.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| College/Faculty: | Schools (1998 to 2008) > School of Medicine | |||||||||
| School or Department: | Institute of Cardiovascular Sciences | |||||||||
| Funders: | British Heart Foundation | |||||||||
| Subjects: | Q Science > QP Physiology | |||||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/7203 |
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