Applications are invited for a British Heart Foundation-funded PhD studentship to start in October 2015 (or soon thereafter). The project will be supervised by Dr Alan Stewart and Dr Samantha Pitt in the School of Medicine.
Irregular blood clotting is a prevalent cause of morbidity and premature death in the UK. Zinc ions (Zn2+) are important regulators of normal haemostasis following release from activated platelets. Also in certain disease states the available plasma Zn2+ pool may be altered such as to trigger pathological clotting mechanisms. Fibrinogen and histidine-rich glycoprotein (HRG) can regulate coagulation through Zn2+-dependent binding and neutralisation of heparins, a natural anticoagulant. Low molecular weight heparins (LMWHs) are also used clinically to treat thrombosis and have more predictable dose-effect profiles than unfractionated heparin (UFH). We have found that Zn2+ enhances HRG-mediated neutralisation of UFH but not LMWHs. It is unknown whether Zn2+ exerts similar effects upon binding of fibrinogen to different heparins.
Here we will characterise interactive binding of Zn2+ and various forms of heparin to fibrinogen and determine the likely contributions of both proteins to Zn2+-dependent heparin neutralisation in vivo. We will also establish the degree to which physiological and pathophysiological processes may influence Zn2+ binding to HRG and fibrinogen. A third aim is to determine the relative degree to which fibrinogen and HRG neutralise different heparins in response to increased Zn2+ in the context of fibrin clot formation. Collectively, the results of this study will provide important information relating to pathological clotting and the use of heparin-based drugs.
The successful candidate will be based in the Medical and Biological Sciences Building at the heart of the St Andrews science campus. The student will gain experience in a range of laboratory techniques including protein production, purification and biochemical analysis using a variety of assay systems. Training will be further enhanced by participation in GRADskills, an extensive and award-winning generic skills development programme for early stage researchers at the university.
Informal enquiries can be addressed to Dr Alan Stewart (E-mail: [Email Address Removed]). For more information please see the group website at https://synergy.st-andrews.ac.uk/metalion/
The studentship is funded for 3 years with a tax-free stipend starting at £19,919 per annum. Tuition fees at the Home/EU rate will also be paid. There is no provision for overseas student fees.
We are looking for enthusiastic candidates who hold a first or upper-second class degree (or equivalent, e.g. MSc) in Chemistry, Biochemistry or a related subject from a recognised academic institution. To apply, please visit the University of St Andrews website and download the PhD application form. Full details are given here: http://www.st-andrews.ac.uk/study/pg/apply/research/.
Kassaar O., Schwarz-Linek U., Blindauer C.A., Stewart A.J. (2015) Plasma free fatty acid levels influence Zn2+-dependent histidine-rich glycoprotein-heparin interactions via an allosteric switch on serum albumin. J. Thromb. Haemost. 13: 101-110.
Kassaar O., McMahon S.A., Thompson R., Botting C.H., Naismith J.H., Stewart A.J. (2014) Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: Implications for angiogenic regulation. Blood 123: 1948-1955.
Barnett J.P., Blindauer C.A., Kassaar, O., Khazaipoul S., Martin E.M., Sadler P.J., Stewart A.J. (2013) Allosteric modulation of zinc speciation by fatty acids. Biochim. Biophys. Acta 1830: 5456-5464.