Dr Graeme Stasiuk G.Stasiuk@hull.ac.uk
Senior Lecturer in Molecular Imaging
Is zinc a critical modulator of cyclic nucleotide signalling?
People Involved
Dr Simon Calaminus S.Calaminus@hull.ac.uk
Project Description
inc (Zn2+) deficiency is present in multiple conditions from obesity to cancer. However importantly Zn2+ deficiency can lead to a bleeding phenotype.In this proposal we investigate how Zn2+ is important for the control of platelet cyclic nucleotide signalling. This is critical to understand as cyclic nucleotide signalling elevation can produce a bleeding phenotype, whilst a reduction can lead to a prothrombotic phenotype. Our pilot data demonstrates that Zn2+ chelation inhibits both platelet aggregation to U46619 and platelet spreading on fibrinogen in washed and platelet rich plasma. We propose underlying this inhibition is an elevation in cyclic nucleotide signalling, as our data indicate that in resting platelets, treatment with Zn2+ chelators led to an elevation of cAMP and pVASPser157 phosphorylation. Furthermore Zn2+chelation can potentiate the action of PGI2, at dose close to physiological significance, demonstrating that this could be the mechanism by which Zn2+ chelation elevates the risk of bleeding. This elevation of PKA signalling observed in vitro could indicate that Zn2+ plays a key role in the switching off platelet inhibitory signalling and therefore could be part of the mechanism that explains why Zn2+ deficiency in vivo leads to a bleeding diathesis
| Status | Project Complete |
|---|---|
| Funder(s) | British Heart Foundation |
| Value | £108,740.00 |
| Project Dates | Oct 1, 2019 - Dec 31, 2022 |
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