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Title: Glycoprotein receptor mediated regulation of platelet morphology
Author: Calaminus, Simon
ISNI:       0000 0001 3514 2576
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2007
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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.
Supervisor: Not available Sponsor: British Heart Foundation (BHF)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology