Heart failure (HF) remains a major cause of death with worse 5-year survival than all forms of cancer combined. This project seeks to understand the mechanisms that underlie two important contributing factors to death in HF patients; i) contractile failure and, ii) the increased propensity for arrhythmias. Both contractile dysfunction and an increased propensity for arrhythmias are associated with the mis-regulation of intracellular calcium. Moreover, the function of many calcium regulatory proteins is modified by their phosphorylation status, which is determined by a family of enzymes known as the phosphodiesterases (PDEs, of which there are at least 11 isoform families). PDEs control the turnover of the cyclic nucleotides cAMP and cGMP and thereby set the phosphorylation status of calcium regulatory proteins. Additionally, PDE activity is itself regulated by the levels of cAMP and cGMP; for example in some cases they are inhibited by cGMP and in others activated by cGMP. PDE-5 inhibitors (e.g. Viagra) are best known for their role in treating erectile dysfunction and this is achieved through their ability to raise intracellular cGMP. However, our current data demonstrates a marked survival benefit accruing as a result of PDE-5 inhibition in HF. Furthermore, PDE-5 inhibition restores the hearts sensitivity to catecholamines (adrenergic stimulation) which is lost in HF. The major focus of this project will be the role of phosphodiesterases (PDEs;) in HF and in how chronic inhibition of PDE-5 leads to improved survival and enhanced responsiveness to catecholamines in HF. Preliminary data is consistent with PDE-5 inhibitors influencing the activity of other PDEs within the heart and thence the catecholamine mediated phosphorylation status of calcium regulatory proteins. Exploring the PDE signalling network, its effect on calcium homeostasis and how this is firstly perturbed in HF and then restored by PDE-5 inhibitors is the goal of this project.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree and / or Masters degree in cardiovascular biology or a closely related field. Candidates with experience in in vivo techniques are encouraged to apply.
Training/techniques to be provided:
In Vivo
The post requires that a Home Office Personal Licence is obtained (following a provided Training Course) and that the candidate undertakes certain in vivo procedures. Full training is provided in these areas (and those below) and the candidate will be part of a large and highly experienced team.
In Vitro
Cell isolation by enzymatic digestion, cellular assessment of intracellular calcium concentration using confocal and epifluorescent microscopy, qPCR, cloning, Western blotting, immunohistochemistry, biochemical assays including ELISA and radio-ligand binding assays.
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