Dr K Dibb, Prof A Trafford, Prof D Eisner
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Similarly to the ventricle, contraction in the atria of the heart is brought about by a rise in intracellular Ca2+. The force of contraction is increased physiologically by activation of protein kinase A (PKA; via cAMP) which activates key targets including Ca2+ handling proteins and this process has been extensively studied. Protein kinase G (PKG; activated by cGMP) however also targets Ca2+ handling proteins although far less is known about its function.
Phosphodiesterases (PDEs) hydrolyze the cyclic nucleotides cGMP and cAMP and thereby modulate PKA and PKG activity in cardiac tissue (1). Within the working myocardium the role of PDEs modulating cAMP has been extensively studied and has been subject to clinical trials for heart failure although these were unsuccessful. The importance of PDEs targeting cGMP, specifically PDE5, has been long recognised as a treatment for erectile dysfunction and PDE5 inhibition is currently being investigated as a potential therapy for HF.
Despite the emerging beneficial role of PDE5 inhibition in the ventricle in HF, the consequences of PDE5 inhibition on atrial excitation contraction coupling and ion channel function remain unknown. Interestingly a recent epidemiological study reported that patients with atrial fibrillation are less likely to die from all cause mortality when taking a PDE5 inhibitor (2). Our preliminary data also shows differences in the way that PDE5 inhibition affects systolic Ca2+ in the atria compared to the ventricle. This project aims to understand the functional consequences of PDE5 inhibition in atrial cells and if these could inhibit cellular correlates of arrhythmias.
The experimental questions that this project will aim to answer are:
1) How does acute PDE5 inhibition modify atrial Ca homeostasis and is this pro-arrhythmic at a cellular level?
2) By what pathway are the effects of PDE5 mediated?
3) Does PDE5 treatment decrease the susceptibility of the atria to atrial fibrillation?
Dr Katharine Dibb
https://www.research.manchester.ac.uk/portal/en/persons/katharine-dibb
Division of Cardiovascular Science
http://www.cardiovascular.manchester.ac.uk/about-us/
Funding Notes
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form, full details on how to apply can be found on our website https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mrc-dtp/.
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
1) Knight W and Yan C. Future Med Chem.5(14):1607-1620 2013.
2) Anderson et al Heart 2016