Date of Award

5-2014

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Tia E. Keyes

Second Supervisor

Professor Niamh Moran

Third Supervisor

Professor Robert J. Forster

Funder/Sponsor

This work was funded by the HRB in Ireland under Grant No PHD/2007/11

Keywords

Ruthenium, RGD, Integrin, Platelets, Gold, Arrays

Abstract

Integrin αIIbβ3 is the central protein in haemostasis and thrombosis; its activation is the first step in a cascade of biochemical processes which leads to platelet activation, spreading and clotting. The mechanism of integrin activation and molecular details of platelet activation are still being worked out so tools which aid in this process are useful in both diagnostic and therapy development. Many questions remain on the conformational changes in the key integrin responsible for stimulating thrombosis and methods of preventing or forcing adhesion of platelets on solid surfaces is key in medical devices and diagnostics respectively.

This work exploits the RGD peptide sequence (recognises fibrinogen which plays a key role in platelet activation), for both exploring conformational status of αIIbβ3 integrin in solution and tracking it in platelets and also for binding and releasing platelets from substrates.

The former focusses on novel ruthenium(II) polypyridyl metal complex probes with long luminescent lifetimes which through changes to their photophysics and anisotropy can be used to determine the activation status of an integrin. In addition, the application of two stokes shifted probes: ruthenium(II) polypyridyl complexes, developed in this programme and also a near infra-red BODIPY in neurological tissue imaging is reported. Ru(II)binding to β-amyloid protein aggregates (linked to Alzheimer’s disease) is also presented, proving that the application of ruthenium complexes in biology is diverse, presenting huge potential in a wide variety of areas including tissue imaging and diagnostics.

The latter focusses on novel means of binding or preventing binding of human blood platelets to planar or nanostructured surfaces which through chemical or geometrical modifications can be used to alter the binding ability, morphology and activation status of platelets, an aspect which is vital towards managing thrombus related diseases.

Overall, this thesis introduces some new probes and tools which may have significant value and insight to offer in study and prevention of thrombosis.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

4.50 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2014.

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