Prof A Mathie
No more applications being accepted
Funded PhD Project (European/UK Students Only)
About the Project
Supervisory team: Professor Alistair Mathie, Ms Emma Veale, Professor Ghazwan Butrous, Professor Norbert Weissmann (University of Giessen, Germany).
Background:
HIV infected patients have a > 10 fold higher incidence of pulmonary hypertension compared to the general population (e.g. Syed & Sani 2013, Heart 99 1146-1153), however the reason(s) underlying this is not clear. Recently the importance of the two-pore-domain potassium channel, TASK1, in pulmonary hypertension has been highlighted following the identification of an association between mutations in TASK1 and the disease in patients (Ma et al 2013, NEJM 369, 351-361). It is known that there is significant structural homology between the HIV-1 accessory protein Vpu and the N terminus of TASK1 and that the two proteins interact to disrupt each other’s function (Hsu et al 2004, Mol Cell 14, 259-267; Veale and Mathie unpublished observations). In this project, we aim to determine the importance of this interaction in altering the functional properties of pulmonary arterial smooth muscles cells (PASMCs). This work is part of a larger international collaborative initiative to understand the mechanisms underlying the increased risk of pulmonary hypertension following HIV infection.
Objectives:
Using molecular biological, immunohistochemical and electrophysiological approaches, this project aims to characterise the regulation of TASK1 channels in PASMCs by expression of Vpu. The project will ask: 1) What functional changes in PAMSCs are seen when exposed to Vpu (either expressed from cDNA or recombinant Vpu protein) 2) Are TASK1 channels and expressed Vpu protein co-localised in PASMCs? 3) Are TASK1 channels functionally regulated by recombinant Vpu protein both in expression systems and in PASMCs? 4) Is there protein-protein interaction between TASK1 and Vpu and, if so, what specific amino acids in TASK1 interact with Vpu?
Funding Notes
This position is a University of Kent 50th Anniversary Scholarship and provides tuition fees, plus a maintenance allowance, for UK and EU nationals only. Applicants should possess (or expect to possess by the summer of 2015) at least an upper second class honours degree, or equivalent, in a subject related to the project. Experience in electrophysiology is desirable but not essential. The project will commence in September 2015.
Interested applicants should send a CV and cover letter to Professor Alistair Mathie ([Email Address Removed]).
References
Recent Related Publications:
Mathie A, Veale EL (2015) Two pore domain potassium channels: potential therapeutic targets for the treatment of pain. Pflügers Archiv - Eur J Physiol doi 10.1007/s00424-014-1655-3.
Veale EL, Al Moubarak E, Bajaria N, Omoto K, Cao L, Tucker SJ, Stevens EB, Mathie A (2014). Influence of the N-terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels. Mol Pharmacol 85: 671-681.
Veale EL, Hassan M, Walsh Y, Al Moubarak E, Mathie A (2014). Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome. Mol Pharmacol 85: 397-407.
El Hachmane MF, Rees KA, Veale EL, Sumbayev VV, Mathie A (2014). Enhancement of TWIK-related acid sensitive potassium channel 3 (TASK3) two pore domain potassium channel activity by TNFalpha. J Biol Chem 289: 1388-1401.
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