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Role of plasma fatty acid and zinc dynamics in platelet functioning: Implications for pathological clotting


Project Description

Zinc is an essential micronutrient that is required for many biological processes including control of coagulation. When platelets become activated they release zinc, which in turn binds to plasma proteins and cell surface receptors to regulate clotting. Currently we do not understand how zinc gets into platelets, how it is stored or how these processes may be altered in diseases associated with abnormal clotting. Elevated plasma free fatty acid (FFA) levels are associated with conditions such as cancer, obesity and diabetes, which also increase the risk of developing thrombotic blood clots. Our studies suggest that high levels of FFAs disrupt zinc handling in the blood potentially leading to thrombotic complications.

The specific aims of this project are to:
1. Examine zinc storage, compartmentalisation and flux in platelets.
2. Identify the zinc homeostatic machinery in platelets.
3. Examine the effects of FFA-mediated dysregulation of plasma zinc on platelet functioning.

The successful candidate will be based in the School of Medicine at the heart of the St Andrews Science Campus at North Haugh. The student will receive training in a very wide range of cellular and analytical techniques. Specifically, methodologies will include platelet isolation, cell culture, cellular imaging (of zinc, calcium, specific proteins/organelles) and targeted gene knockdown using shRNA. In addition, quantitative PCR, western blotting and ICP-MS techniques will be used to measure gene expression, protein expression and zinc flux, respectively. As well as laboratory training the student will be encouraged to hone their other scientific skills. It is a requirement of the University of St Andrews that postgraduate students attend the University’s GRADskills programme. This is an award-winning transferable skills programme, which includes courses relating to scientific communication, thesis/research article writing and statistics. They are also required to regularly present their work across schools and to attend external scientific meetings.

We are looking for enthusiastic candidates who hold a first or upper-second class degree (and/or an MSc/MRes degree) in Molecular or Cellular Biology, Biochemistry, Chemistry or a related subject from a recognised academic institution. Applicants with some degree of laboratory research experience are particularly encouraged to apply. To apply, please visit the University of St Andrews website and download the PhD application form. Full details on how to apply are given here: http://www.st-andrews.ac.uk/study/pg/apply/research/

Funding Notes

The studentship is funded as a British Heart Foundation PhD studentship, to start as soon as possible, 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.

References

Sobczak A.I.S., Katundu K.G., Phoenix F., Khazaipoul S., Yu R., Lampiao F., Stefanowicz F., Blindauer C.A., Pitt S.J., Smith T.K., Ajjan, R.A., Stewart A.J. (2019) Plasma non-esterified fatty acids contribute to increased coagulability in type-2 diabetes through altered plasma zinc speciation. bioRxiv 744482.

Coverdale J.P.C., Arya S., Khazaipoul S., Stewart A.J., Blindauer C.A. (2019) Crosstalk between zinc and fatty acids in plasma. BBA – Mol. Cell Biol. Lipids 1864: 532-542.

Reilly-O’Donnell B., Robertson G.B., Karumbi A., McIntyre C., Bal W., Nishi M., Takeshima H., Stewart A.J., Pitt S.J. (2017) Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage. J. Biol. Chem. 292: 13361-13373.

https://synergy.st-andrews.ac.uk/metalion/

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